EP2336161A2 - Oligomères de beta(1-42 amyloïdes, dérivés de ceux-ci et anticorps destinés à ceux-ci, procédé de fabrication et utilisation de ces composés - Google Patents

Oligomères de beta(1-42 amyloïdes, dérivés de ceux-ci et anticorps destinés à ceux-ci, procédé de fabrication et utilisation de ces composés Download PDF

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EP2336161A2
EP2336161A2 EP10179281A EP10179281A EP2336161A2 EP 2336161 A2 EP2336161 A2 EP 2336161A2 EP 10179281 A EP10179281 A EP 10179281A EP 10179281 A EP10179281 A EP 10179281A EP 2336161 A2 EP2336161 A2 EP 2336161A2
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protein
oligomer
amyloid
oligomers
antibody
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EP2336161A3 (fr
EP2336161B1 (fr
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Heinz Hillen
Andreas Striebinger
Carsten Krantz
Achim Moeller
Reinhold Mueller
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AbbVie Deutschland GmbH and Co KG
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Abbott GmbH and Co KG
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    • C07ORGANIC CHEMISTRY
    • C07KPEPTIDES
    • C07K14/00Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • C07K14/435Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • C07K14/46Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates
    • C07K14/47Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates from mammals
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    • C07ORGANIC CHEMISTRY
    • C07KPEPTIDES
    • C07K14/00Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • C07K14/435Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • C07K14/46Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates
    • C07K14/47Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates from mammals
    • C07K14/4701Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates from mammals not used
    • C07K14/4711Alzheimer's disease; Amyloid plaque core protein
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00Medicinal preparations containing peptides
    • A61K38/16Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/17Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • A61K38/1703Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates
    • A61K38/1709Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates from mammals
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00Medicinal preparations containing antigens or antibodies
    • A61K39/0005Vertebrate antigens
    • A61K39/0007Nervous system antigens; Prions
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00Medicinal preparations containing antigens or antibodies
    • A61K39/395Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00Drugs for disorders of the nervous system
    • A61P25/28Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00Drugs for immunological or allergic disorders
    • A61P37/02Immunomodulators
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    • C07KPEPTIDES
    • C07K16/00Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
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    • C07ORGANIC CHEMISTRY
    • C07KPEPTIDES
    • C07K16/00Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
    • C07K16/005Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies constructed by phage libraries
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    • C07ORGANIC CHEMISTRY
    • C07KPEPTIDES
    • C07K16/00Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
    • C07K16/18Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
    • GPHYSICS
    • G01MEASURING; TESTING
    • G01NINVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N33/00Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
    • G01N33/48Biological material, e.g. blood, urine; Haemocytometers
    • G01N33/50Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
    • G01N33/68Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving proteins, peptides or amino acids
    • G01N33/6893Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving proteins, peptides or amino acids related to diseases not provided for elsewhere
    • G01N33/6896Neurological disorders, e.g. Alzheimer's disease
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00Medicinal preparations containing antigens or antibodies
    • A61K2039/57Medicinal preparations containing antigens or antibodies characterised by the type of response, e.g. Th1, Th2
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    • C07ORGANIC CHEMISTRY
    • C07KPEPTIDES
    • C07K2317/00Immunoglobulins specific features
    • C07K2317/70Immunoglobulins specific features characterized by effect upon binding to a cell or to an antigen
    • C07K2317/76Antagonist effect on antigen, e.g. neutralization or inhibition of binding
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    • C07ORGANIC CHEMISTRY
    • C07KPEPTIDES
    • C07K2317/00Immunoglobulins specific features
    • C07K2317/90Immunoglobulins specific features characterized by (pharmaco)kinetic aspects or by stability of the immunoglobulin
    • C07K2317/92Affinity (KD), association rate (Ka), dissociation rate (Kd) or EC50 value
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    • C07ORGANIC CHEMISTRY
    • C07KPEPTIDES
    • C07K2319/00Fusion polypeptide
    • C07K2319/30Non-immunoglobulin-derived peptide or protein having an immunoglobulin constant or Fc region, or a fragment thereof, attached thereto
    • GPHYSICS
    • G01MEASURING; TESTING
    • G01NINVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N2333/00Assays involving biological materials from specific organisms or of a specific nature
    • G01N2333/435Assays involving biological materials from specific organisms or of a specific nature from animals; from humans
    • G01N2333/46Assays involving biological materials from specific organisms or of a specific nature from animals; from humans from vertebrates
    • G01N2333/47Assays involving proteins of known structure or function as defined in the subgroups
    • G01N2333/4701Details
    • G01N2333/4709Amyloid plaque core protein

Definitions

  • the invention also relates in the same way to derivatives of the oligomers, in particular crosslinked oligomers and oligomers based on truncated forms of the amyloid ⁇ (1-42) protein thereof, their preparation and their use.
  • Amyloid ⁇ (1-42) protein also referred to as A ⁇ (1-42)
  • a ⁇ is a central component of insoluble extracellular deposits (senile or neuritic plaques) composed of proteins, lipids, carbohydrates and salts in the brains of Alzheimer's disease and Down syndrome patients ( CL Masters et al. PNAS 82, 4245-4249, 1985 ).
  • This protein which tends to polymerize in an aqueous environment, can exist in very different molecular forms.
  • a ⁇ (1-42) -protofibrils are postulated. These are still soluble, fibrillar, more aggregated A ⁇ (1-42) forms with molecular weights in the range of 150-250 kDa ( Arispe et al. PNAS 90. 567 (1993 ) Lashuel et al., Nature 418, 291 (2002 )), which due to pore-forming properties should cause an uncontrolled influx of calcium through the membranes of neuronal cells.
  • oligomeric A ⁇ (1-42) derivatives having molecular weights in the range of 15-30 kDa ( MP Lambert et al. PNAS 95, 6448-6453 (1998 )). These also as amyloid-derived, diffusible and contributing to dementia ligands (ADDL's for Amyloid Derived Dementing Ligands, see. US-A 6,218,506 and WO 01/10900 , or for Amyloid Derived Diffusive Ligands, cf. Lambert et al. supra ), non-fibrillar oligomers are found in preparations which have an inhibitory effect on the long-term potentiation rate of neurons in hippocampal slices.
  • ADDL's for Amyloid Derived Dementing Ligands see. US-A 6,218,506 and WO 01/10900
  • non-fibrillar oligomers are found in preparations which have an inhibitory effect on the long-term potentiation rate of neurons in hippocampal slices.
  • At least two forms are discussed which, when subjected to gel electrophoretic analysis under non-denaturing conditions, have molecular weights in the range of from 27 to 28 kDa and 23 to 24 kDa ( US-A 6,218,506 ) or from about 26 kDa to 28 kDa ( WO 01/10900 ) or 17 kDa and 27 kDa ( MP Lambert et al. PNAS 95, 6448-6453 (1998 ) and SDSgelel electrophoretic analysis under denaturing conditions molecular weights of 17 kDa and 22 kDa ( MP Lambert et al.
  • a disadvantage of the described manufacturing instructions is that they give inhomogeneous oligomer preparations.
  • a ⁇ (1-42) responsible for neuromodulation have not yet been reproducibly provided, let alone unambiguously identified.
  • N-terminally truncated forms of the A ⁇ (1-42) protein has been mentioned in connection with Alzheimer's disease.
  • N-terminal truncated forms were detected in the deposits of brains of deceased Alzheimer's patients in addition to A ⁇ (1-42) ( C. Masters et al., PNAS 82, 4245-4249 (1985 )).
  • certain proteases occurring in the brain such as neprilysin (NEP 24.11) or IDE (short for "insulin degrading enzymes" can degrade A ⁇ (1-42) ( DJ Selkoe, Neuron 32, 177-180, (2001 )).
  • Antibodies directed against monomeric A ⁇ (1-42) protein and certain fragment thereof have already been described.
  • the object of the present invention which is to provide the neuromodulatory and in particular neurone-damaging effect of A ⁇ (1-42) causative and in dementia diseases, such as Alzheimer's disease and Down's syndrome, increasingly occurring molecular forms, solves the invention by certain A ⁇ (1-42) oligomers obtainable in the form of homogeneous preparations with a specific process from monomeric A ⁇ (1-42) protein, as well as by certain derivatives of these oligomers, in particular cross-linked oligomers and oligomers based on truncated A ⁇ ( 1-42) forms.
  • the preparation process makes it possible to convert poorly aqueous-soluble, peptide-synthetic A ⁇ (1-42) protein into defined soluble oligomers in high yield.
  • the present invention therefore relates to the objects defined in the patent claims.
  • the present invention relates to oligomers of the amyloid ⁇ (1-42) protein, wherein the oligomers in SDS gel electrophoresis have an apparent molecular weight of about 15 kDa, 20 kDa, 38 kDa and 48 kDa, respectively, or derivatives of the oligomers an optionally modified derivatization according to the molecular weight.
  • Amyloid ⁇ (1-42) protein is a 42 amino acid polypeptide derived from amyloid precursor protein (APP) by proteolytic processing.
  • APP amyloid precursor protein
  • Isoforms of the amyloid ⁇ (1-42) protein thereto which occur in other organisms than humans, especially other mammals, especially rats.
  • the present invention relates to oligomers of human amyloid ⁇ (1-42) proteins.
  • Human amyloid ⁇ (1-42) proteins include in particular the protein having the amino acid sequence SEQ ID NO: 1, as well as muteins and allelic variants thereof, which are derived from said sequence, in particular by amino acid exchange.
  • amino acid substitutions should be mentioned: A21 G, E22K, E22Q, E22G and D23N.
  • the muteins or allelic variants of the amyloid ⁇ (1-42) protein according to the invention include, in particular, proteins having an amino acid sequence SEQ ID NO: 1 in which one or more amino acids selected from alanine 21, glutamic acid 22 and aspartic acid 23 other, preferably selected from glycine, lysine, glutamine and asparagine, amino acid are substituted.
  • amino acids selected from alanine 21, glutamic acid 22 and aspartic acid 23 other preferably selected from glycine, lysine, glutamine and asparagine, amino acid are substituted.
  • substitutions at position 22, in particular with glutamine or glycine are substitutions at position 22, in particular with glutamine or glycine.
  • Rat amyloid ⁇ (1-42) proteins include, in particular, the protein having the amino acid sequence SEQ ID NO: 2, as well as muteins and allelic variants thereof, which are derived from said sequence, in particular by amino acid exchange.
  • amino acid substitutions are to be mentioned, which correspond to the explained for the human sequence amino acid substitutions.
  • the oligomers of the invention are obtainable by oligomerization of amyloid ⁇ (1-42) protein.
  • the oligomerization involves a noncovalent aggregation of monomeric amyloid protein, so that it can be assumed that the oligomers according to the invention are composed of several amyloid ⁇ (1-42) protein monomers.
  • the oligomers according to the invention have different molecular weights.
  • apparent molecular weights can be assigned to the oligomers. These are about 15 kDa for the oligomer A1, about 20 kDa for the oligomer A2, about 38 kDa for the oligomer B1 and about 48 kDa for the oligomer B2, when gel electrophoresis under standard denaturing conditions (Tris-glycine gel, 4-20%, cf.
  • Lambli UK Nature 227, 680-685 (1970 ), wherein the following standard proteins have the same apparent molecular weights under the same conditions: myosin 250 kDa, bovine serum albumin 98 kDa, glutamine hydrogenase 64 kDa, carboanhydrase 36 kDa, myoglobin 30 kDa, lysozyme 16 kDa, aprotinin 6 kDa, insulin B chain 4 kDa (see Blue Pre-stained Standard).
  • the molecular weights for the oligomers B are about 64 to 90 kDa when subjected to gel electrophoresis under standard native conditions (Tris-glycine gel, 4-20%), the following standard proteins having the same apparent molecular weights under the same conditions: myosin 250 kDa, bovine serum albumin 98 kDa, glutamine hydrogenase 64 kDa, carboanhydrase 36 kDa, myoglobin 30 kDa, lysozyme 16 kDa, aprotinin 6 kDa, insulin B chain 4 kDa (see Blue Pre-stained Standard).
  • the oligomers of the invention are characterized by an affinity for neuronal cells. It is believed that the oligomers bind to certain cell surface proteins, particularly receptors.
  • the oligomers of the invention are characterized by a neuromodulating effect.
  • This neuromodulating effect can manifest itself in particular in a reduced survival capacity of neuronal cells, for example neuroblastoma cells (neurotoxicity), if at least one oligomer according to the invention is allowed to act on a culture of these cells.
  • the viability of the cells can be assessed in a manner known per se, for example by determining the extent of apoptosis caused by the action of the oligomers according to the invention. Suitable test methods, for example colorimetric methods based on 3- [4,5-dimethylthiazol-2-yl] -2,5-diphenyltetrazolium bromide (MTT), are available for this purpose.
  • this neuromodulating effect can be manifested in particular in a modulation of the firing rate of neurons.
  • oligomer according to the invention in the manner described above, e.g. in the form of one of the above-mentioned compositions.
  • the cells or cellular structures are expediently provided in vitro, in particular as cell culture or, in the case of cellular structures, also as homogenates.
  • Neuronal cells and in particular neuroblastoma cells serve to determine neurotoxicity.
  • the cells may also be in vivo, especially as part of an organism, e.g. an experimental animal, or ex vivo.
  • the condition of the cells is usually determined at least once before and at least once after exposure to the oligomer. If a comparison between the state before and the state after the action indicates a deviation, the tested oligomer has activity.
  • the type of condition to be determined depends on the type of activity to be determined.
  • Neurotoxicity can be determined by, for example, determining the survivability. For this purpose one can determine the proportion of living cells based on the total cell number before and after the action of the oligomer and compare with each other.
  • the method is carried out at least twice, once in the presence of the test substance and once again without test substance.
  • the test substance is added to the oligomers usually after their provision.
  • the substance is expediently added even before the formation of the oligomers, ie even before their preparation, for example the educt (s) used for the oligomer formation.
  • the preparation process of the invention with the addition of the test substance and then determine whether and to what extent the oligomers are formed. For this purpose, one can determine whether the process products obtained in this way have the properties of the oligomers according to the invention, that is, for example, have their molecular weight, binding capacity and activity.
  • the oligomers B of the invention are to be preferred. Derivatives of these oligomers are also preferred in this respect, with particular emphasis on the oligomers based on an N-terminally shortened A ⁇ (1-42) protein.
  • the oligomers A and the oligomers B may be obtained as a mixture in the form of compositions which in addition to the oligomers also low levels of other polypeptides, in particular monomeric amyloid ⁇ (1-42) protein and optionally also higher molecular forms aggregated amyloid - ⁇ (1-42) protein.
  • Such compositions are likewise provided by the present invention and are distinguished, in particular, by the fact that the proportion of oligomer (s) according to the invention based on the totality of the proteins derived from the amyloid ⁇ (1-42) protein is at least 70% by weight. %, preferably at least 90 wt .-% and in particular at least 95 wt .-% is.
  • the proportion of the oligomer A2 (20 kDa band in the SDS gel) is at least 50% by weight and preferably at least 70% by weight and in particular at least 85% by weight.
  • the proportion of the oligomers B1 and B2 (38 kDa and 48 kDa bands in the SDS gel) is at least 60 wt .-%, preferably at least 75 wt .-% and in particular at least 90 wt .-%.
  • the oligomers of the invention may also be derivatized.
  • the purpose of such derivatizations may be, for example, to modulate the physicochemical properties of the oligomers, in particular with regard to bioavailability, to provide the oligomers with a detectable label or to immobilize, for example, to be coupled to the carrier. Labeling and immobilization are particularly important for diagnostic applications.
  • Suitable markers well known in the protein biochemical field are well known to the person skilled in the art. These include fluorescence labels, for example certain fluorescein and tetramethylrhodamine derivatives, luminescent labels, colorimetric labels, radioactive labels and magnetic labels, and labels with affinity for complementary binding partners, such as biotin and streptavidin derivatives.
  • the oligomer derivatives have molecular weights which may be correspondingly increased in comparison to the underivatized oligomers, but the aggregation number is the same.
  • a biotin derivative based on the A ⁇ (1-42) oligomer B1 having a molecular weight in the 38 kDa SDS gel has a molecular weight of 42 kDa.
  • Such cross-linked oligomers have the advantage that they are stabilized and their oligomerization is generally no longer reversible. They are therefore particularly suitable for use in diagnostic test systems or as an immunogen for the production of oligomer-specific antibodies.
  • oligomers of the invention also include oligomers of fragments of the amyloid ⁇ (1-42) protein.
  • Preferred are those fragments obtainable by the action of naturally occurring proteases.
  • the fragments obtainable by proteolysis under non-denaturing conditions in physiological buffers have increased proteolytic stability compared to the amyloid ⁇ (1-42) protein.
  • Preference is given to fragments obtainable by the action of endopeptidases.
  • the fragments are obtainable by the action of trypsin, chymotrypsin, thermolysin, elastase, papain or endoproteinase GluC.
  • those fragments are preferred whose oligomers according to the invention by a neuromodulating Effect are marked.
  • preferred fragments are characterized in particular by being derived from the amyloid ⁇ (1-42) protein by cleavage of N-terminal sequences.
  • these N-terminal sequences may be fragments of up to 23, preferably up to 21 and most preferably up to 19 amino acids of the N-terminal sequence of the amyloid ⁇ (1-42) protein.
  • preference is given to fragments of the A ⁇ (1-42) protein whose sequence comprises amino acids 24 to 42, preferably 22 to 42 and in particular 20 to 42, in continuous sequence.
  • the N-terminal sequences to be cleaved may be sequences having at least 7, preferably at least 9, and most preferably at least 11 amino acids of the N-terminal sequence of the amyloid ⁇ (1-42) protein.
  • fragments of the amyloid ⁇ (1-42) protein are preferred, which are shortened N-terminally by 7 to 23, preferably 9 to 21 and in particular 11 to 19 amino acids. These fragments correspond to the formula A ⁇ (x-42), where x is 8 to 24, preferably 10 to 22 and especially 12 to 20.
  • Derivatives of the invention also include those derived from an amyloid ⁇ (1-42) protein having C-terminal 1 or 2 further amino acids.
  • oligomers of the A ⁇ (1-43) protein or the above include corresponding derivatives thereof.
  • the process according to the invention for the preparation of the oligomers may comprise essentially three steps, of which the first step is optional but advantageous, the second step for the preparation of the oligomers A and B is mandatory and the third step is the preparation of the oligomers B according to the invention.
  • Step 1 concerns the unfolding of the protein.
  • hydrogen bond-breaking agents such as hexafluoroisopropanol (HFIP)
  • DMSO dimethyl sulfoxide
  • the stock suspension can be temporarily stored at low temperature, for example at about -20 ° C.
  • the protein can be taken up in a slightly acidic, preferably aqueous solution, for example an about 10 mM aqueous HCl solution. After an incubation period of generally a few minutes, insoluble constituents are centrifuged off. A few minutes at 10,000 g are appropriate. These process steps are preferably carried out at room temperature, i. a temperature in the range of 20 to 30 ° C performed. The supernatant obtained after centrifugation contains the amyloid ⁇ (1-42) protein and can be temporarily stored at low temperature, for example at about -20 ° C.
  • Step 2 relates to the oligomerization of the protein to the oligomers A.
  • a detergent is allowed to act on the optionally at least partially unfolded protein until sufficient oligomer A is formed.
  • ionic detergents in particular anionic detergents.
  • Detergents of the formula (I) in which R is unbranched alkyl are advantageous, of which in particular alk-1-yl radicals may be mentioned. Particularly preferred is sodium dodecyl sulfate (SDS). Also lauric acid and oleic acid can be used advantageously. Particularly advantageous are the Na salt of the detergent is lauroylsarcosine (also known as sarkosyl NL-30 or Gardol ®).
  • the exposure time of the detergent depends on whether - and if so, to what extent - the protein introduced into the oligomerization is unfolded. If the protein according to step 1 previously treated with a hydrogen bond-breaking agent, ie in particular with hexafluoroisopropanol, sufficient exposure times in the range of a few hours, advantageously about 1 to 20 and in particular about 2 to 10 hours then when the exposure temperature about 20 to 50 ° C and in particular about 35 to 40 ° C. If less or essentially unfolded protein is assumed, correspondingly longer exposure times are expedient.
  • a hydrogen bond-breaking agent ie in particular with hexafluoroisopropanol
  • amyloid ⁇ (1-42) protein has been pretreated according to the procedure outlined above as an alternative to step 1, or if it is entered directly in step 2, exposure times will range from about 5 to 30 hours and more preferably from about 10 to 20 hours then when the exposure temperature is about 20 to 50 ° C and especially about 35 to 40 ° C. After incubation, insoluble constituents are advantageously centrifuged off. A few minutes at 10,000 g are appropriate.
  • the selected detergent concentration depends on the detergent used. When SDS is used, a concentration in the range of 0.01 to 1% by weight, preferably 0.05 to 0.5% by weight, for example, about 0.2% by weight, proves useful. If lauric acid or oleic acid are used, somewhat higher concentrations are expedient, for example in a range from 0.05 to 2% by weight, preferably from 0.1 to 0.5% by weight, for example from about 0.5% by weight. %.
  • the action of the detergent should be at a salt concentration approximately in the physiological range.
  • NaCl concentration in the range of 50 to 500 mM, preferably 100 to 200 mM and especially at about 140 mM are useful.
  • the oligomers A ie in particular the oligomers A1 and / or A2 containing solution can be temporarily stored at low temperature, for example at about -20 ° C.
  • it can be fed to the oligomers B according to the invention or the further reaction, or further work-up or purification steps can initially follow, with which, in particular, a further enrichment of at least one the oligomers A of the invention is achieved.
  • the oligomers according to the invention can be separated from further protein constituents which contain the solution and in particular those which are derived from the amyloid ⁇ (1-42) protein.
  • affinity chromatographic methods are suitable for this purpose, in which, for example, specific antibodies, ie in particular also the oligomer-specific antibodies according to the invention, can be used.
  • Step 3 relates to the oligomerization to the oligomers B.
  • a composition containing oligomer A is selected as starting material for this step.
  • the oligomers A have meaning according to the invention as intermediates for the preparation of the oligomers B. If this composition comes from step 2, it regularly contains detergent and a salt concentration in the physiological range. Then it is appropriate to reduce the detergent effect or the salt concentration. This can be achieved by reducing the detergent or salt concentration, e.g. by dilution, conveniently with water or a buffer of lower salt concentration, eg. B. Tris-HCl, pH 7.3, take place.
  • Dilution factors in the range of about 2 to 10, advantageously in the range of about 3 to 8 and in particular of about 4 have been found to be suitable.
  • the reduction of detergency can also be achieved by the addition of substances which can neutralize detergency.
  • substances capable of complexing the detergents such as substances capable of stabilizing cells in the course of purification and extraction procedures, e.g. certain EO / PO block copolymers, in particular the block copolymer guided under the trade name Pluronic® F 68.
  • alkoxylated and in particular ethoxylated alkylphenols such as the ethoxylated t-octylphenols of the Triton® X series, in particular Triton® X100, 3- (3-cholamidopropyl-dimethylammonio) -1-propanesulfonate (CHAPS®) or alkoxylated and in particular ethoxylated sorbitan fatty acid esters such as those of the Tween® series, in particular Tween® 20, in concentration ranges in the range or above the respective critical micelle concentration.
  • ethoxylated alkylphenols such as the ethoxylated t-octylphenols of the Triton® X series, in particular Triton® X100, 3- (3-cholamidopropyl-dimethylammonio) -1-propanesulfonate (CHAPS®) or alkoxylated and in particular ethoxylated sorbitan
  • the solution is incubated until sufficient oligomer B has formed. Exposure times in the range of several hours, preferably in the range of about 10 to 30 hours and in particular in the range of about 15 to 25 hours are sufficient if the exposure temperature about 20 to 50 ° C and in particular about 35 to 40 ° C. Then you can concentrate the solution and spin off any residues. Again, prove to be a few minutes at 10,000 g as appropriate. The supernatant obtained after centrifugation contains oligomers B.
  • the oligomers B may first be precipitated from the detergent-containing solution, recovered and redissolved in detergent-free medium. Measures for precipitation of proteins are well known to those skilled in the art. According to the invention, the addition of aqueous methanolic acetic acid has proven to be expedient. Without being bound by any particular mechanism, detergent or salt variation appears to bring the protein into definite soluble forms which clearly differ from the starting form of the protein dissolved in aqueous physiological buffers, e.g. by denaturing or native gel electrophoresis or gel permeation chromatography. This is surprising since detergents normally disaggregate protein aggregates, i. H. subdivided into subunits, whereas according to the invention, starting from a monomer tending to aggregate defined oligomers are obtained.
  • the crosslinking of oligomers according to the invention or derivatives thereof can be carried out in a manner known per se. If, for example, glutaric dialdehyde is used as the crosslinking agent, one from process step 2 according to the invention can be used or 3 resulting solution with a glutaric dialdehyde solution. After a few hours at room temperature, the oligomers reacted with the glutaraldehyde. The reaction can then be stopped in a manner known per se by reacting the excess glutaric dialdehyde with reagents generally known for this purpose, such as ethanolamine. Depending on whether the oligomers A or B according to the invention are cross-linked, a solution of crosslinked oligomers according to the invention which are denoted by A-CL or B-CL is obtained.
  • the optionally cross-linked oligomers B or derivatives thereof it is possible, following their synthesis, to increase the salt concentration again without impairing the stability of the oligomers. This is important in view of the use of the oligomers, for example in the case that in use physiological conditions are appropriate (cellular applications, in vivo applications).
  • oligomers of fragments of the amyloid ⁇ (1-42) protein can be prepared by proteolysis, either starting from corresponding monomer fragments by oligomerization or starting from oligomers of the amyloid ⁇ (1-42) protein.
  • a solution resulting from the process steps 2 or 3 according to the invention can be treated with protease.
  • the protease is inactivated in a generally known manner.
  • the resulting oligomers can then be obtained on the basis of procedures already described here and, if necessary, further processed by further work-up or purification steps.
  • novel oligomers and the compositions containing them are characterized by their homogeneity and stability. They are soluble in physiological media, eg, physiological saline, and differ from fibrillar forms in their more globular appearance. They have the advantage of having a spatial structure that differs markedly from other A ⁇ (1-42) forms, especially the monomer, non-toxic oligomers, the A ⁇ (1-42) APP precursor molecule, protofibrils and fibrils. They are therefore particularly suitable for the generation of specific antibodies both in vivo and in vitro and allow, for example, a specific active immunization. It may be crucial to use for immunization only those oligomers that are responsible for the disease.
  • a ⁇ (1-42)
  • the monomeric molecule or smaller oligomers may be necessary for important signaling functions in the organism be.
  • the removal of the fibrillar deposits, which are believed to be important for the lining of the cells, can damage the organism.
  • oligomers of the invention possess diagnostic and therapeutic value due to their involvement in amyloid ⁇ -protein associated physiological processes.
  • the use of oligomers according to the invention and derivatives thereof, optionally in the form of a corresponding composition, in diagnostic in vitro and in vivo detection methods is the subject of the present invention.
  • Amyloid ⁇ -protein-associated physiological processes include those associated with deposition of amyloid proteins (amyloidoses). These include both those processes that lead to structural changes of nerve tissue and are important, for example, in Alzheimer's disease and Down's syndrome, as well as those processes that affect other tissues, such as amyloid microangiopathies, such as Congophilic amyloid angiopathy (CAA ).
  • amyloidoses include those associated with deposition of amyloid proteins (amyloidoses). These include both those processes that lead to structural changes of nerve tissue and are important, for example, in Alzheimer's disease and Down's syndrome, as well as those processes that affect other tissues, such as amyloid microangiopathies, such as Congophilic amyloid angiopathy (CAA ).
  • CAA Congophilic amyloid angiopathy
  • the oligomers according to the invention based on truncated forms of the A ⁇ (1-42) protein are of particular importance: because of the lacking N-terminus, a significantly more selective immune response can be generated with them than with the A ⁇ (1-42) protein. While the highly immunogenic N-terminus in the classical A ⁇ (1-42) protein predominantly results in antibodies specific for this region of the molecule, eg the antibodies 6E10 (F.
  • One aspect of this use is the generation of oligomer-specific antibodies as part of a therapy.
  • a further object of the present invention is the use of an oligomer or derivative thereof according to the invention in the therapeutic field, in particular as a vaccine.
  • Such a vaccine is usually a pharmaceutical composition containing at least one oligomer according to the invention and / or at least one derivative thereof according to the invention.
  • a pharmaceutical composition containing at least one oligomer according to the invention and / or at least one derivative thereof according to the invention.
  • one of the inventive, two or more oligomer-containing compositions, or a combination of different compositions can be used.
  • the composition may contain a physiologically acceptable carrier and optionally other excipients, for example immunostimulants.
  • the vaccines according to the invention can be formulated in particular in a form suitable for parenteral, for example intravenous, intramuscular and subcutaneous administration.
  • the carrier preferably contains water, saline, alcohol, a fat, a wax and / or a buffer.
  • an adjuvant may be included.
  • Most adjuvants contain a substance intended to protect the antigen from rapid catabolism, such as aluminum hydroxide or a mineral oil, as well as lipid A, Bortadella pertussis or Mycobacterium tuberculosis-derived protein.
  • Suitable adjuvants are usually commercially available, for example complete or incomplete Freund's adjuvant; AS-2; Aluminum salts such as aluminum hydroxide (optionally gel) or aluminum phosphate; Calcium, iron or zinc salts; an insoluble suspension of acylated tyrosine; acylated sugars; cationically or anionically derivatized polysaccharides; polyphosphazenes; biodegradable microspheres; Monophosphoryl lipid A.
  • Cytokines such as GM-CSF or interleukin-2, -7 or -12 can also be used as adjuvants.
  • oligomers or oligomer derivatives to be used are not or only weakly immunogenic, their immunogenicity can be increased by adding them to carriers, preferably a carrier protein, such as keyhole limpet hemocyanin (KLH), limulus polyphenus hemocyanin ((LPH), Bovine serum albumin (BSA) or ovalbumin (OVA), for example, may be useful to those skilled in the art, such as reaction with glutaric dialdehyde, for example by incubation of the oligomer or oligomer mixture with a suitable peptide or peptide mixture in water or an aqueous solvent.
  • KLH keyhole limpet hemocyanin
  • LPH limulus polyphenus hemocyanin
  • BSA Bovine serum albumin
  • OVA ovalbumin
  • This reaction may conveniently be carried out at ambient temperature, usually room temperature, but it may also be convenient to cool or slightly heat it, usually within a few hours to the desired result, a reaction time of, for example 2 h is in the
  • the components to be used are first combined. It is advantageous to first incubate the resulting component mixture. This is conveniently done at ambient temperature, usually at room temperature. However, it may be convenient to cool or slightly heat the mixture. The incubation period is usually a few minutes to a few hours, an incubation period of 1 h has proved to be advantageous.
  • immunization cocktails will generally contain other adjuvants, especially adjuvants commonly used for immunization, e.g. Freund's adjuvant.
  • adjuvants commonly used for immunization e.g. Freund's adjuvant.
  • complete Freund's adjuvant is used for the first immunization whereas all further immunizations are performed with incomplete Freund's adjuvant.
  • the antigen preferably as a component mixture described above, is added to the excipient (s). As a rule, the antigen is emulsified.
  • Rodents or even rabbits are particularly suitable as hosts. These or other suitable hosts are injected with the immunization cocktails, preferably subcutaneously.
  • the antibody titers can be determined by an immunoassay, for example, competitive with a sheep anti-host IgG and labeled oligomer.
  • a particular host is suitable for antibody production. For example, if four immunizations are performed, one can determine the antibody titer after the third immunization and then obtain antibodies from animals that have sufficient antibody titer.
  • B lymphocytes Part of a mammalian immune system is B lymphocytes, which as a whole contain an antibody repertoire composed of hundreds of millions of different antibody specificities.
  • a normal immune response against a particular antigen means the selection of one or more antigen-specifically binding antibodies from that repertoire, and the success of an immune response is based, at least in part, on the ability of those antibodies to specifically recognize (and eventually eliminate) the stimulatory antigen. while ignoring other molecules from the environment of the antibodies.
  • the antigen of interest may be allowed to act on the antibody repertoire either in vivo or in vitro .
  • the antigen is allowed to act on the repertoire by immunizing an animal with the antigen in vivo .
  • This in vivo approach may further involve establishing a series of hybridomas from the lymphocytes of an animal and selecting a hybridoma which secretes an antibody specifically binding the antigen.
  • the animal to be immunized may be, for example, a mouse, rat, rabbit, chicken, camelid or sheep or a transgenic version of any of the aforementioned animals, for example, a human immunoglobulin gene transgenic mouse that makes human antibodies to an antigenic stimulus.
  • mice with severe combined immunodeficiency that have been reconstituted with human peripheral blood mononuclear cells (chimeric hu-PBMC-SCID mice) or with lymphoid cells or progenitors thereof, as well as Mice treated with lethal whole body irradiation, then protected against radiation with bone marrow cells from a mouse with severe combined immunodeficiency (SCID) and subsequently transplanted with functional human lymphocytes (the so-called Trimera system).
  • SCID severe combined immunodeficiency
  • Another type of animal to be immunized is an animal (eg, a mouse) in the genome of which an endogenous gene encoding the antigen of interest has been knocked out, eg, by homologous recombination, such that this animal is immunized with the antigen recognizes the antigen as foreign.
  • an animal eg, a mouse
  • an endogenous gene encoding the antigen of interest has been knocked out, eg, by homologous recombination, such that this animal is immunized with the antigen recognizes the antigen as foreign.
  • the polyclonal or monoclonal antibodies produced by these methods can be characterized and selected using known screening techniques, including, but not limited to, ELISA techniques.
  • the antigen is allowed to act on the antibody repertoire in vitro by screening a recombinant antibody library with the antigen.
  • the recombinant antibody library may be expressed on the surface of bacteriophages or on the surface of yeast cells or on the surface of bacterial cells.
  • the recombinant antibody library is, for example, an scFv library or a Fab library.
  • antibody libraries are expressed as RNA-protein fusions.
  • the antigen can be allowed to act on the antibody repertoire by immunizing an animal with the antigen in vivo, and then recombinant antibody library or single domain antibody library (eg, heavy and / or light chain) prepared from lymphoid cells of the animal Antigen screent in vitro .
  • the antigen is allowed to act on the antibody repertoire by immunizing an animal with the antigen in vivo and then affinity maturing a recombinant antibody library or single domain library prepared from lymphoid cells of the animal.
  • the antigen is allowed to act on the antibody repertoire by immunizing an animal with the antigen in vivo , then selecting individual antibody-producing cells which secrete an antibody of interest and recovering from these selected cells cDNAs for the heavy and light chain variable region (eg by PCR) and the heavy and light variable regions Chain is expressed in vitro in mammalian host cells (referred to as the lymphocyte antibody selection method, or SLAM for "Selected Lymphocyte Antibody Method"), allowing the selected antibody gene sequences to be further selected and manipulated.
  • monoclonal antibodies can be selected by expression cloning by expressing the heavy and light chain antibody genes in mammalian cells and selecting those mammalian cells which secrete an antibody of the desired binding affinity.
  • those polyclonal and monoclonal antibodies can be selected which bind an oligomer or derivative thereof, but not other forms of the A (1-42) protein, APP, amyloid fibrils or amyloid plaques and a number of other unrelated antigens and tissues ,
  • the person skilled in the art is well aware that antibody selections are based on well-defined antigens. However, if less well-defined antigens are used, they are not selective enough. In short, in vitro exposure and selection are similar to affinity chromatography, separating "ligands" for the desired antigen from those that do not bind the antigen with sufficient affinity. The degree of enrichment of the desired antibodies from the vast pool of other antibodies is therefore a direct consequence of antigen quality.
  • the oligomers and derivatives thereof according to the invention are antigens with which appropriate, relevant and selective antibodies accumulate and effectively separate from antibodies which recognize other forms related to the A (1-42) protein as well as other unrelated antigens to let.
  • monoclonal antibodies can be isolated by standard techniques, such as those originally developed by Kohler and Milstein (1975, Nature 256: 495-497 ) (see also Brown et al. (1981) J. Immuno / 127: 539-46 ; Brown et al. (1980) J Biol Chem 255: 4980-83 ; Yeh et al. (1976) PNAS 76: 2927-31 ; and Yeh et al. (1982) Int. J. Cancer 29: 269-75 ) described hybridoma technique.
  • an immortalized cell line (typically a myeloma) is fused with lymphocytes (typically splenocytes or lymph node cells or peripheral blood lymphocytes) of a mammal immunized with the oligomer or derivative thereof of the invention, and the culture supernatants of the resulting hybridoma cells are screened to identify a hybridoma which a monoclonal antibody having specificity for oligomer according to the invention or for a derivative thereof produced.
  • lymphocytes typically splenocytes or lymph node cells or peripheral blood lymphocytes
  • the immortalized cell line eg, a myeloma cell line
  • the immortalized cell line is derived from the same mammalian species as the lymphocytes.
  • murine hybridomas can be established by fusing lymphocytes from a mouse immunized with an immunogenic preparation of the invention to an immortalized mouse cell line.
  • Preferred immortalized cell lines are mouse myeloma cell lines which are sensitive to hypoxanthine, aminopterin and thymidine-containing culture medium (HAT medium).
  • myeloma cell lines can be used as standard by fusion, eg the P3-NS1 / 1-Ag4-1, P3-x63-Ag8.653 or Sp2 / O-Ag14 myeloma line.
  • These myeloma cell lines are available from the American Type Culture Collection (ATCC), Rockville, MD.
  • ATCC American Type Culture Collection
  • HAT-sensitive mouse myeloma cells are fused to mouse splenocytes using polyethylene glycol (PEG).
  • PEG polyethylene glycol
  • the from the Fusion-resultant hybridoma cells are then selected using HAT medium, killing unfused and non-productively fused myeloma cells (unfused splenocytes die after several days as they are untransformed).
  • Monoclonal antibody-producing hybridoma cells specifically recognizing oligomer or derivative thereof of the present invention are identified by screening the hybridoma culture supernatants for such antibodies, eg, by using a standard ELISA assay to select those antibodies, the oligomer of the invention or a derivative thereof can specifically bind.
  • mice can be used for in vivo immunization.
  • a host expressing an endogenous version of the antigen of interest itself may be used.
  • a host deficient for an endogenous version of the antigen of interest may be used. It has been shown, for example, that mice made deficient for a particular endogenous protein (ie, knockout mice) via homologous recombination on the corresponding endogenous gene produce a humoral response to the protein with which they were immunized, and thus to produce high affinity monoclonal antibodies
  • Antibodies to the protein can be used (see, eg Roes, J. et al. (1995) J. Immunol. Methods 183: 231-237 ; Lunn, MP et al. (2000) J. Neurochem. 75: 404-412 ).
  • non-human mammals are useful as hosts for antibody production. These include mice, rats, chickens, camelids, rabbits and goats (and knockout versions thereof), although mice are preferred for hybridoma production.
  • non-human host animal expressing a human antibody repertoire.
  • Such non-human animals include transgenic animals (e.g., mice) carrying human immunoglobulin transgenes (chimeric hu-PBMC-SCID mice) and human / mouse irradiation chimeras, described in more detail below.
  • the animal immunized with an oligomer or derivative thereof of the invention is a non-human mammal, preferably a mouse, that is transgenic by human immunoglobulin genes such that the non-human mammal makes human antigens following an antigenic stimulus.
  • human immunoglobulin genes such that the non-human mammal makes human antigens following an antigenic stimulus.
  • heavy and light chain human immunoglobulin immunoglobulin transgenes are introduced into such animals with the human germline configuration Animals have been altered so that their endogenous loci for heavy and light chain are inactive. Stimulating such animals with antigen (eg, with a human antigen) produces antibodies derived from the human immunoglobulin sequences (ie, human antibodies). From the lymphocytes of such animals, human monoclonal antibodies can be made by standard hybridoma technology.
  • the animal immunized with the oligomer or derivative thereof of the invention may be a severe combined immunodeficiency (SCID) mouse reconstituted with human peripheral blood mononuclear cells or lymphoid cells or progenitors thereof.
  • SCID severe combined immunodeficiency
  • Such mice termed chimeric hu-PBMC-SCID mice, have been shown to produce human immunoglobulin responses to an antigenic stimulus.
  • chimeric hu-PBMC-SCID mice have been shown to produce human immunoglobulin responses to an antigenic stimulus.
  • the animal which is immunized with oligomer according to the invention or a derivative thereof is a mouse which is lethal Irradiated with bone marrow cells from mice with severe combined immunodeficiency (SCID) and then transplanted with functional human lymphocytes.
  • SCID severe combined immunodeficiency
  • This type of chimera called the Trimera system, is used to make human monoclonal antibodies by immunizing the mice with the antigen of interest and then producing monoclonal antibodies using standard hybridoma technology.
  • these mice and their use for the production of antibodies see for example Eren, R. et al. (1998) Immunology 93: 154-161 ; Reisner, Y and Dagan, S. (1998) Trends Biotechnol. 16: 242-246 ; Ilan, E. et al. (1999) Hepatology 29: 553-562 ; and Bocher, WO et al. (1999) Immunology 96: 634-641 ,
  • antibodies according to the invention can be identified and isolated by screening recombinant immunoglobulin library combiners with an oligomer or derivative thereof according to the invention, thus members of the immunogiobulin library specific to the oligomer or derivative thereof, to isolate.
  • Kits for generating and screening display banks are commercially available (eg, the Recombinant Phage Antibody System from Pharmacia, Catalog No. 27-9400-01, and the SurfZAP® Phage Display Kit from Stratagene, Catalog No. 240612).
  • the display bank is an scFv bank or a fab bank. The phage display technique for screening recombinant antibody libraries has been well described.
  • WO 97/29131 (describes the preparation of a recombinant human Antibody to a human antigen (human tumor necrosis factor alpha), as well as in vitro affinity maturation of the recombinant antibody) and Salfeld et al. US Provisional Application No. 60 / 126,603 and the patent applications based thereon (also describes the production of recombinant human antibodies to human antigen (human interleukin-12), as well as the in vitro affinity maturation of the recombinant antibody).
  • recombinant antibody libraries can be expressed on the surface of yeast cells or bacterial cells.
  • Methods for making and screening benches that are expressed on the surface of yeast cells are known in U.S. Pat WO 99/36569 described.
  • Methods for making and screening banks that are expressed on the surface of bacterial cells are known in U.S. Pat WO 98/49286 described in more detail.
  • the DNAs encoding the antibody light and heavy chains are isolated by standard molecular biology techniques, for example, by PCR amplification of DNA from the display package (eg, the phage) isolated during the screening of the bank.
  • Nucleotide sequences of genes for light and heavy antibody chains, with which PCR primers can be prepared, are known in the art. Many such sequences are for example in Kabat, EA, et al. (1991) Sequences of Proteins of Immunological Interest, Fifth Edition, U.S. Department of Health and Human Services, NIH Publication No. 91-3242 and the database for sequences of the human germ line VBASE.
  • An antibody or antibody portion of the invention may be produced by recombinantly expressing the genes for immunoglobulin light and heavy chains in a host cell.
  • a Host cell is transfected with one or more recombinant expression vectors bearing DNA fragments encoding the antibody light and heavy immunoglobulin chains such that the light and heavy chains are expressed in the host cell and preferably into the medium in which the host cells are cultured; be secreted. From this medium, the antibodies can be obtained.
  • Standardized recombinant DNA methodology is used to obtain genes for heavy and light antibody chains, to insert these genes into recombinant expression vectors, and to introduce the vectors into host cells.
  • DNA fragments encoding the VH and VL segments of the antibody of interest can be further manipulated with standard recombinant DNA techniques, such as the variable region genes in full length antibody chain genes To convert genes for Fab fragments or into a scFv gene.
  • a VL or VH-encoding DNA fragment is operatively linked to another another protein, e.g. linked to a constant antibody region or a flexible linker, encoding DNA fragment.
  • the term "operatively linked” is intended to mean that the two DNA fragments are linked together in such a way that the amino acid sequences encoded by the two DNA fragments remain in-frame.
  • the isolated DNA encoding the VH region can be converted into a full-length heavy chain gene by encoding the VH region-encoding DNA with another DNA heavy chain constant region (CH1, CH2 and CH3) operatively linked.
  • CH1, CH2 and CH3 DNA heavy chain constant region
  • the sequences of human heavy chain constant region genes are well known (see, eg Kabat, EA, et al. (1991) Sequences of Proteins of Immunological Interest, Fifth Edition, U.S. Department of Health and Human Services, NIH Publication No. 91-3242 ), and DNA fragments spanning these regions can be obtained by standard PCR amplification.
  • the heavy chain constant region may be a constant region of IgG1, IgG2, IgG3, IgG4, IgA, IgE, IgM or IgD, with a constant region of IgG1 or IgG4 being preferred.
  • the VHcoding DNA can be operatively linked to another DNA molecule which only codes for the constant region CH1 of the heavy chain.
  • the isolated DNA encoding the VL region can be converted into a full-length light chain gene (as well as a Fab light chain gene) by mixing the VL-encoding DNA with another, the CL constant region Chain-coding DNA molecule operatively linked.
  • the sequences of human light chain constant region genes are well known (see Kabat, EA, et al. (1991) Sequences of Proteins of Immunological Interest, Fifth Edition, U.S. Department of Health and Human Services, NIH Publication No. 91-3242 ), and DNA fragments spanning these regions can be obtained by standard PCR amplification.
  • the constant region of the light chain may be a constant kappa or lambda region, with a constant kappa region being preferred.
  • the VH and VL-encoding DNA fragments can be operatively linked to another fragment that encodes a flexible linker, eg, the amino acid sequence (Gly 4 -Ser) 3 , such that the VH and VL Sequences are expressed as a continuous single-chain protein, with the VL and VH regions linked together via the flexible linker (see Bird et al. (1988) Science 242: 423-426 ; Huston et al. (1988) Proc. Natl. Acad. Sci. USA 85: 5879-5883 ; McCafferty et al., Nature (1990) 348: 552-554 ).
  • a flexible linker eg, the amino acid sequence (Gly 4 -Ser) 3
  • VH and VL single domains having specificity for oligomer of the invention or a derivative thereof can be isolated from single domain libraries by the methods described above.
  • Two VH single domain chains (with or without CH1) or two VL chains or a pair of VH and VL chains of the desired specificity can be used to remove oligomers or derivatives thereof of the invention from the body.
  • the DNAs encoding the partial and full length light and heavy chains can be inserted into expression vectors such that the genes are operably linked to transcriptional and translational control sequences.
  • operably linked is intended to mean that an antibody gene is ligated in a vector such that transcriptional and translational control sequences within the vector fulfill their intended function of regulating the transcription and translation of the antibody gene.
  • the expression vector and expression control sequences are chosen to be compatible with the expression host cell used.
  • the gene for the The antibody light chain and antibody heavy chain gene can be inserted into separate vectors, or both genes are inserted into the same expression vector, which is the usual case.
  • the antibody genes are inserted into the expression vector by standard methods (eg, ligation of complementary restriction sites on the antibody gene fragment and vector, or blunt-ended ligation if no restriction sites are present).
  • the expression vector may already carry constant antibody region sequences.
  • one approach is to convert the VH and VL sequences into full-length antibody genes by inserting them into expression vectors that already encode the heavy or light chain constant regions, such that the VH segment is linked to the one or more CH segment (s) within the vector is operatively linked, and also the VL segment is operatively linked to the CL segment within the vector.
  • the recombinant expression vector may encode a signal peptide that facilitates secretion of the antibody chain from the host cell.
  • the antibody chain gene can be cloned into the vector such that the signal peptide in reading frame is linked to the N-terminus of the antibody chain gene.
  • the signal peptide may be an immunoglobulin signal peptide or a heterologous signal peptide (ie, a signal peptide from a non-immunogiobulin protein).
  • the expression vectors of the invention may have regulatory sequences which control the expression of the genes for the antibody chain in a host cell.
  • the term "regulatory sequence” is intended to include promoters, enhancers, and other expression control elements (eg, polyadenylation signals) that control the transcription or translation of the antibody chain genes.
  • regulatory sequences are, for example, in Goeddel; Gene Expression Technology: Methods in Enzymology 185, Academic Press, San Diego, CA (1990 ).
  • regulatory sequences for expression in mammalian host cells include viral Elements that lead to high protein expression in mammalian cells, such as promoters and / or enhancers derived from cytomegalovirus (CMV) (such as the CMV promoter / enhancer), simian virus 40 (SV40) (such as the SV40 promoter / enhancer). , Adenovirus (eg, the Adenovirus Major Late Promoter AdMLP) and Polyoma
  • CMV cytomegalovirus
  • SV40 simian virus 40
  • Adenovirus eg, the Adenovirus Major Late Promoter AdMLP
  • Polyoma For further description of viral regulatory elements and sequences thereof, see eg U.S. Patent No. 5,168,062 from Stinsky, U.S. Patent No. 4,510,245 by Bell et al. and U.S. Patent No. 4,968,615 Schaffner et al.
  • the recombinant expression vectors of the invention may have additional sequences, such as sequences that regulate replication of the vector in host cells (eg, origins of replication) and selectable marker genes.
  • the selectable marker genes facilitate the selection of host cells into which the vector has been introduced (see, eg U.S. Patent No. 4,399,216 . 4,634,665 and 5,179,017 , all by Axel et al .).
  • Preferred selectable marker genes include the gene for dihydrofolate reductase (DHFR) (for use in dhfr - host cells with methotrexate selection / amplification) and the neo gene (for G418 selection).
  • DHFR dihydrofolate reductase
  • the expression vector (s) encoding the heavy and light chains are transfected into a host cell using standard techniques.
  • the various forms of the term "transfection" are intended to cover a variety of techniques commonly used to introduce exogenous DNA into a prokaryotic or eukaryotic host cell, eg, electroporation, calcium phosphate precipitation, DEAE-dextran transfection, and the like.
  • the antibodies of the invention While it is theoretically possible to express the antibodies of the invention in either prokaryotic or eukaryotic host cells, expression of the antibodies is preferred in eukaryotic cells, and particularly in mammalian host cells, since the likelihood that a correctly folded and immunologically active antibody will be assembled and secreted in such eukaryotic cells and in particular mammalian cells is higher than in prokaryotic cells. Prokaryotic expression of antibody genes has been reported to be ineffective for the production of high yields of active antibody ( Boss, MA and Wood, CR (1985) Immunology Today 6: 12-13 ).
  • the antibodies When recombinant expression vectors encoding the antibody genes are introduced into mammalian host cells, the antibodies are produced by culturing the host cells until the antibody expresses in the host cells, or preferably the host cell Antibodies are secreted into the culture medium in which the host cells grow.
  • the antibodies can be recovered from the culture medium using standardized methods for the purification of proteins.
  • Host cells may also be used to produce portions of intact antibodies, such as Fab fragments or scFv molecules. Variations of the procedure described above are of course part of the invention. For example, it may be desirable to transfect a host cell with DNA encoding either the light chain or the heavy chain (but not both) of an antibody of the invention. If light or heavy chains are present which are not required for the binding of the antigen of interest, the DNA encoding either or both of such a light or heavy chain may be partially or completely removed by recombinant DNA technology. Molecules expressed by such truncated DNA molecules also belong to the antibodies of the invention.
  • bifunctional antibodies may be prepared in which one heavy and one light chain are an antibody of the invention and the other heavy and light chains have specificity for any antigen other than the antigen of interest by subjecting an antibody of the invention to a second antibody by standard chemical methods cross-linked.
  • a recombinant expression vector encoding both the heavy antibody chain and the light antibody chain is introduced into dhff-CHO cells by calcium phosphate-mediated transfection.
  • the heavy and light antibody chain genes are each operably linked to CMV enhancer / AdMLP promoter regulatory elements to effect strong transcription of the genes.
  • the recombinant expression vector also carries a DHFR gene with which CHO cells transfected with the vector can be selected by using methotrexate selection / amplification. The selected transformed host cells are cultured so that the heavy and light antibody chains are expressed, and intact antibody is recovered from the culture medium.
  • a covalent fusion is generated by in vitro translation of synthetic mRNAs carrying at their 3 'end puromycin, a peptidyl acceptor antibiotic, between an mRNA and the peptide or protein that it encodes.
  • a specific mRNA from a complex mixture of mRNAs may be enriched for the oligomer of the invention or a derivative thereof based on the properties of the encoded peptide or protein (eg antibody or portion thereof) such as the binding of the antibody or portion thereof become.
  • Antibody or portion thereof-encoding nucleic acid sequences obtained from screening such benches can be expressed by recombinant means in the manner described above (eg, in mammalian host cells) and further subject to further affinity maturation by either mRNA peptide in subsequent rounds By introducing mutations into the originally selected sequence (s), or by using other methods of in vitro affinity maturation of recombinant antibodies in the manner described above.
  • the antibodies of the invention may also be prepared using a combination of in vivo and in vitro approaches, such as methods in which first an oligomer of the invention or a derivative thereof is allowed to act on an antibody repertoire in vivo in a host animal in order to stimulate the production of oligomer or derivative binding antibodies, and then the further antibody selection and / or antibody maturation (ie optimization) is accomplished by one or more in vitro techniques.
  • such a combined method may involve first immunizing a non-human animal (eg, a mouse, rat, rabbit, chicken, camelid, goat or transgenic version thereof or a chimeric mouse) with the oligomer or derivative thereof of the invention to one To stimulate antibody response to the antigen, and then to produce and screen a phage display antibody library using immunoglobulin sequences from lymphocytes stimulated in vivo by the action of the oligomer or derivative.
  • the first step of this combined approach may be performed in the manner described above in the context of the in vivo approaches, while the second step of this approach may be performed in the manner described above in connection with the in vitro approaches.
  • Preferred methods for hyperimmunization of non-human animals followed by in vitro screening of phage display banks prepared from the stimulated lymphocytes include those described by BioSite Inc., see, eg WO 98/47343 . WO 91/17271 .
  • U.S. Patent No. 5,427,908 and U.S. Patent No. 5,580,717 are described.
  • a combined method involves first obtaining a non-human animal (eg, a mouse, rat, rabbit, chicken, camelid, goat, or a knockout and / or transgenic version thereof, or a chimeric mouse) with a subject of the invention
  • a non-human animal eg, a mouse, rat, rabbit, chicken, camelid, goat, or a knockout and / or transgenic version thereof, or a chimeric mouse
  • Oligomer or derivative thereof is immunized to stimulate an antibody response against the oligomer or derivative thereof, and the lymphocytes producing the antibodies with the desired specificity are selected by screening (for example, hybridomas prepared from the immunized animals).
  • the genes for the antibodies or single domain antibodies are isolated from the selected clones (by standard cloning methods, such as the reverse transcriptase polymerase chain reaction) and subjected to in vitro affinity maturation to thereby enhance the binding properties of the selected antibody or antibodies.
  • the first step of this approach may be accomplished in the manner described above in the context of the in vivo approaches, while the second step of this approach may be accomplished in the manner described above in connection with the in vitro approaches, in particular by Methods for in vitro affinity maturation used, such as those described in WO 97/29131 and WO 00/56772 are described.
  • the recombinant antibodies are generated from single isolated lymphocytes using a procedure known to those skilled in the art as Lymphocyte Antibody Selection (SLAM) methods
  • SAM Lymphocyte Antibody Selection
  • a non-human animal eg a mouse, rat, rabbit, chicken, camelid, goat, or a transgenic version thereof, or a chimeric mouse
  • a non-human animal eg a mouse, rat, rabbit, chicken, camelid, goat, or a transgenic version thereof, or a chimeric mouse
  • individual antibody-secreting cells are selected using an antigen-specific hemolytic plaque assay.
  • the oligomer or derivative thereof, or structurally related molecules of interest can be coupled to sheep erythrocytes using a linker such as biotin, thereby allowing individual cells secreting antibodies of appropriate specificity to be identified using the hemolytic plaque assay.
  • variable regions are recovered from the cells by reverse transcriptase PCR, and these variable regions can then be ligated in conjunction with appropriate immunoglobulin constant regions (eg, human constant regions ) in mammalian host cells such as COS or CHO cells.
  • appropriate immunoglobulin constant regions eg, human constant regions
  • the host cells transfected with the amplified immunoglobulin sequences derived from in vivo selected lymphocytes may then be subjected to further in vitro analysis and selection, for example by spreading the transfected cells to isolate cells expressing antibodies of the desired specificity.
  • the amplified immunoglobulin sequences can be further manipulated in vitro.
  • oligomer-specific antibodies obtainable by the above methods are as well the subject of the present invention as their use for the preparation of a medicament for the treatment of amyloid- ⁇ -associated dementia diseases or for the preparation of a composition for the diagnosis of amyloid- ⁇ -associated dementia diseases.
  • the antibodies obtainable according to the invention also include monoclonal antibodies, in particular chimeric and humanized antibodies, and also oligomer-binding fragments thereof.
  • the present invention relates to proteins and in particular antibodies which specifically bind to an oligomer or derivative thereof according to the invention, i. Antibody with specificity for an inventive oligomer or derivative thereof.
  • the present invention also relates to parts of these proteins or antibodies, in particular antigen-binding parts thereof, i. Protein or antibody parts which bind an oligomer according to the invention or a derivative thereof.
  • the antibody according to the invention is preferably selected such that it has a specific binding kinetics (eg high affinity, low dissociation, low off-rate, strong neutralizing activity) for the specific binding to oligomer or derivative thereof according to the invention.
  • a specific binding kinetics eg high affinity, low dissociation, low off-rate, strong neutralizing activity
  • proteins and in particular antibodies are preferred which bind the oligomer or derivative thereof with higher affinity than monomeric A ⁇ (1-42) protein and / or monomeric A ⁇ (1-40) protein.
  • Affinity ratios of 10, 100 or 1000 are particularly preferred.
  • antibodies of the invention so as to inhibit the activity, particularly the activity neutoxische, inventive oligomers or derivatives thereof having an IC 50 of 1 x 10 -6 M or less.
  • Inhibition constants IC 50 of 1 x 10 -7 M or less, 1 x 10 -8 M or less, 1 x 10 9 M or less, 1 x 10 -10 M or less, or 1 x 10 -11 M or less are specified Order increasingly preferred.
  • the antibodies are preferably isolated antibodies. In another aspect, the antibodies are neutralizing antibodies.
  • the antibodies of the invention include monoclonal and recombinant antibodies. According to many embodiments, the antibody may include an amino acid sequence derived entirely from a single species, such as a human antibody or a mouse antibody. According to further embodiments, the antibody may be a chimeric antibody or a CDR graft antibody or another form of humanized antibody.
  • antibody is intended to refer to immunoglobulin molecules formed from 4 polypeptide chains, two heavy (H) chains, and two light (L) chains.
  • the chains are usually linked together by disulfide bonds.
  • Each heavy chain is composed of a heavy chain variable region (abbreviated herein as HCVR or VH) and a heavy chain constant region.
  • the heavy chain constant region is made up of three domains CH1, CH2 and CH3 formed.
  • Each light chain is composed of a light chain variable region (abbreviated herein as LCVR or VL) and a constant light chain region.
  • the light chain constant region is formed from a domain CL.
  • antibody portion refers to one or more fragments of an antibody having specificity for an oligomer or derivative thereof of the invention, wherein the fragment or fragments are still capable of the oligomer or derivative specifically bind to it. It has been shown that the antigen-binding function of an antibody can be detected by fragments of a complete antibody.
  • binding fragments within the meaning of the term "antigen-binding portion" of an antibody include (i) a Fab fragment, ie a monovalent fragment composed of the VL, VH, CL and CH1 domains; (ii) an F (ab ') 2 fragment, ie a bivalent fragment, which contains two Fab fragments linked together in the hinge region via a disulfide bridge; (iii) an Fd fragment composed of the VH and CH1 domains; (iv) an Fv fragment composed of the FL and VH domains of a single arm of an antibody; (v) a dAb fragment ( Ward et al., (1989) Nature 341: 544-546 ) consisting of a VH domain or VH, CH1, CH2, DH3, or VH, CH2, CH3; and (vi) an isolated complementarity determining region (CDR).
  • a Fab fragment ie a monovalent fragment composed of the VL, VH, CL and CH1 domains
  • the two domains of the Fv fragment, VL and VH are encoded by separate genes, they can further be linked together with a synthetic linker using recombinant techniques, whereby they can be produced as a single protein chain, wherein the VL- and VH regions come together to form monovalent molecules (known as single-chain Fv (ScFv), see eg Bird et al. (1988) Science 242: 423-426 ; and Huston et al. (1988) Proc. Natl. Acad. Sci. USA 85: 5879-5883 ).
  • Single chain antibodies should also be covered by the term "antigen-binding portion" of an antibody.
  • Other forms of single chain antibodies such as “diabodies” are also included.
  • an antibody or antigen-binding portion thereof may be part of a larger immunoadhesive molecule formed by covalent or non-covalent association of the antibody or antibody portion with one or more other proteins or peptides.
  • immunoadhesive molecules include the use of the streptavidin core region to produce a tetrameric scFv molecule ( Kipriyanov, SM, et al. (1995) Human Antibodies and Hybridomas 6: 93-101 ) and the use of a cysteine residue, a marker peptide and a C-terminal polyhistidine tag to make bivalent and biotinylated scFv molecules ( Kipriyanov, SM, et al. (1994) Mol.
  • Antibody parts such as Fab and F (ab ') 2 fragments, can be made from whole antibodies using conventional techniques, such as digestion with papain or pepsin.
  • antibodies, antibody parts and immunoadhesion molecules can be obtained using standard recombinant DNA techniques.
  • An "isolated antibody having specificity for an oligomer or derivative thereof" according to the invention means an antibody having specificity for an oligomer or derivative thereof according to the invention which is substantially free of other antibodies with different antigen specificities, ie in particular an antibody which is free of antibodies, which specifically bind to other forms of the A ⁇ (1-42) protein as described above.
  • neutralizing antibody means an antibody whose binding to a particular antigen results in the inhibition of the biological activity of the antigen. This inhibition of the biological activity of the antigen can be assessed by measuring one or more indicators of the biological activity of the antigen using a suitable in vitro or in vivo assay.
  • the term "monoclonal antibody” means an antibody derived from a hybridoma (e.g., an antibody derived from a hybridoma) Hybridoma technology, as the standard Hybridommethodik after Kohler and Milstein, produced hybridoma is secreted).
  • a hybridoma-derived antibody having specificity for an oligomer or derivative thereof according to the present invention is therefore referred to as a monoclonal antibody.
  • recombinant antibody refers to antibodies produced, expressed, generated or isolated by recombinant means, such as antibodies expressed using a recombinant expression vector transfected into a host cell; Antibodies isolated from a recombinant combinatorial antibody library; Antibody isolated from an animal (eg, a mouse) transgenic by human immunoglobulin genes (see, e.g. Taylor, LD, et al. (1992) Nucl. Acids Res. 20: 6287-6295 ); or antibodies which are produced, expressed, generated or isolated in any other manner in which certain immunoglobulin gene sequences (such as human immunoglobulin gene sequences) are assembled with other DNA sequences.
  • Recombinant antibodies include, for example, chimeric, CDR graft and humanized antibodies.
  • human antibody refers to antibodies whose variable and constant regions are human germline immunoglobulin sequences as described, for example, by Kabat et al. (please refer Kabat, et al. (1991) Sequences of Proteins of Immunological Interest, Fifth Edition, U.S. Department of Health and Human Services, NIH Publication No. 91-3242 ), correspond or derive from it.
  • the human antibodies of the present invention may include amino acid residues that are not encoded by human germ-line immunoglobulin sequences (eg, mutations introduced by in vivo or by somatic mutation in vivo or by viral mutagenesis), for example, in the CDRs, and particularly in CDR3.
  • Recombinant human antibodies of the invention have variable regions and may also include constant regions derived from human germ line immunoglobulin sequences (see Kabat, EA, et al. (1991) Sequences of Proteins of Immunological Interest, Fifth Edition, U.S. Department of Health and Human Services, NIH Publication No. 91-3242 ).
  • such recombinant human antibodies are subjected to in vitro mutagenesis (or if an animal is transgenic through human Ig sequences, in vivo somatic mutagenesis) such that the amino acid sequences of the VH and VL regions are recombinant antibody Sequences, although related to or derived from human germ line VH and VL sequences, do not naturally exist within the human antibody germ line repertoire in vivo.
  • such recombinant antibodies are the result of selective mutagenesis or reverse mutation, or both.
  • reverse mutation refers to a method in which some or all of the somatic mutant amino acids of a human antibody are replaced with the corresponding germline residues of a homologous germline antibody sequence.
  • the heavy and light chain sequences of a human antibody of the invention are separately compared to the germline sequences in the VBASE database to identify the most homologous sequences. Signs in the human antibody of the invention are attributed to the germline sequence by mutating at defined nucleotide positions encoding such aberrant amino acids.
  • the direct or indirect significance of each amino acid for antigen binding thus identified as a candidate for reverse mutation should be examined, and an amino acid which, upon mutation, interferes with a desirable property of the human antibody should not be included in the final human antibody.
  • those amino acid positions which differ from the closest germline sequence but are identical to the corresponding amino acid sequence of a second germline sequence can be kept unchanged, provided that the second germline sequence has the sequence of the human antibody according to the invention is identical and co-linear at least in 10 and preferably in 12 amino acids on both sides of the amino acid in question.
  • Reverse mutations can be made at any stage of antibody optimization.
  • chimeric antibody refers to antibodies that include heavy and light chain variable region sequences from a species, but in which the sequences of one or more of the CDR regions of VH and / or VL with CDR sequences of a are replaced by other species, such as antibodies, which have murine heavy and light chain variable regions in which one or more of the mouse CDRs (e.g., CDR3) are replaced with human CDR sequences.
  • humanized antibody refers to antibodies that contain sequences of the heavy and light chain variable region from a non-human species (e.g., mouse, rat, rabbit, chicken, camelid, goat), but in which at least a portion of the art VH and / or VL sequence has been altered to be more "human-like", i. H. to be more similar to human germ line variable sequences.
  • a non-human species e.g., mouse, rat, rabbit, chicken, camelid, goat
  • VH and / or VL sequence has been altered to be more "human-like", i. H. to be more similar to human germ line variable sequences.
  • One type of humanized antibody is a CDR graft antibody in which human CDR sequences are inserted into non-human VH and VL sequences to replace the corresponding non-human CDR sequences.
  • surface plasmonresonance refers to an optical phenomenon that can be used to analyze biospecific interactions by detecting changes in protein concentrations with a biosensor matrix using, for example, the BlAcore system (Pharmacia Biosensor AB, Uppsala, Sweden and Piscataway, NJ ).
  • BlAcore Pharmacia Biosensor AB, Uppsala, Sweden and Piscataway, NJ .
  • K off refers to the off-rate constant for the dissociation of an antibody from the antibody / antigen complex.
  • K d refers to the dissociation constant of a particular antibody-antigen interaction.
  • the binding affinity of the antibodies of the invention can be assessed using standardized in vitro immunoassays, such as ELISA or BlAcore analyzes.
  • compositions comprising a protein according to the invention and in particular a Antibodies according to the invention and optionally a pharmaceutically acceptable carrier.
  • Pharmaceutical compositions according to the invention may further comprise at least one additional therapeutic agent, e.g. B. one or more additional therapeutic agents for the treatment of a disease, the alleviation of the antibodies of the invention are useful include.
  • the pharmaceutical composition may further include one or more additional therapeutic agents useful for the treatment of diseases in which the activity of the oligomer is important.
  • Pharmaceutically acceptable carriers include all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents, and the like, as long as they are physiologically compatible.
  • Pharmaceutically acceptable carriers include, for example, water, saline, phosphate buffered saline, dextrose, glycerol, ethanol, and the like, as well as combinations thereof.
  • isotonic agents for example, sugars, polyalcohols, such as mannitol or sorbitol, or sodium chloride.
  • Pharmaceutically acceptable carriers may further include minor amounts of auxiliary substances such as wetting or emulsifying agents, preservatives or buffers which increase the shelf life or efficacy of the antibodies.
  • the pharmaceutical compositions may be suitable for parenteral administration, for example.
  • the antibodies are preferably prepared as injectable solutions with an antibody content of 0.1-250 mg / ml.
  • the injectable solutions may be formulated in liquid or lyophilized form in a flint glass or vial, ampoule or filled syringe as a dosage form.
  • the buffer may contain L-histidine (1-50 mM, preferably 5-10 mM) and have a pH of 5.0-7.0, preferably 6.0.
  • Other suitable buffers include, but are not limited to, sodium succinate, sodium citrate, sodium phosphate or potassium phosphate buffer.
  • Sodium chloride may be used to adjust the tonicity of the solution to a concentration of 0-300 mM (preferably 150 mM for a liquid dosage form).
  • Cryoprotectants may be included for a lyophilized dosage form, eg, sucrose (eg 0-10%, preferably 0.5-1.0%). Other suitable cryoprotectants include trehalose and lactose.
  • Fillers can be used for a lyophilized dosage form, for example mannitol (eg 1 - 10%, preferably 2 - 4%).
  • Stabilizers can be used in both liquid and lyophilized dosage forms, eg L-methionine (eg 51-50 mM, preferably 5-10 mM).
  • Suitable bulking agents include glycine and arginine.
  • surfactants may be used, for example polysorbate-80 (eg 0-0.05%, preferably 0.005-0.01%).
  • surfactants include polysorbate-20 and BRIJ surfactants.
  • compositions of the invention can take a variety of forms. These include liquid, semi-solid and solid dosage forms such as liquid solutions (eg injectable and infusible solutions), dispersions or suspensions, tablets, pills, powders, liposomes and suppositories.
  • liquid solutions eg injectable and infusible solutions
  • dispersions or suspensions tablets, pills, powders, liposomes and suppositories.
  • the preferred form depends on the intended mode of administration and therapeutic application.
  • compositions in the form of injectable or infusible solutions are preferred, for example, compositions that are similar to the passive immunization of humans with other antibodies.
  • the preferred route of administration is parenteral (e.g., intravenous, subcutaneous, intraperitoneal, intramuscular).
  • the antibody is administered by intravenous infusion or injection.
  • the antibody is administered by intramuscular or subcutaneous injection.
  • compositions typically must be sterile and stable under the conditions of manufacture and storage.
  • the compositions may be formulated as a solution, microemulsion, dispersion, liposome, or other ordered structure suitable for high drug concentrations.
  • Sterile injectable solutions can be prepared by incorporating the active compound (ie antibody) in the required amount into a suitable solvent, optionally with one or a combination of the above ingredients as needed, and then sterile-filtering.
  • Dispersions are typically prepared by incorporating the active compound in a sterile vehicle containing a base dispersion medium and optionally other ingredients needed.
  • a sterile lyophilized powder for the preparation of sterile injectable solutions vacuum drying and spray drying are preferred methods of preparation by which a powder of the active ingredient and optionally other desirable ingredients are obtained from a previously sterile-filtered solution.
  • the right Flowability of a solution can be maintained by, for example, using a coating such as lecithin, maintaining the required particle size in the case of dispersions, or using surfactants.
  • Prolonged absorption of injectable compositions can be achieved by incorporating an agent which retards absorption, e.g., monostearate salts and gelatin, into the composition.
  • the antibodies of the invention may be administered by a variety of methods known to those skilled in the art, although for many therapeutic applications, subcutaneous injection, intravenous injection or infusion is the preferred mode of administration.
  • the person skilled in the art knows that the route and / or mode of administration depends on the desired result.
  • the active compound may be formulated with a carrier that protects the compound against rapid release, such as a controlled release formulation, including implants, transdermal patches, and microencapsulated delivery systems.
  • a controlled release formulation including implants, transdermal patches, and microencapsulated delivery systems.
  • Biodegradable biocompatible polymers can be used, such as ethylene vinyl acetate, polyanhydrides, polyglycolic acid, collagen, polyorthoesters, and polylactic acid.
  • the methods for preparing such formulations are well known to those skilled in the art, see, for example Sustained and Controlled Release Drug Delivery Systems, JR Robinson, ed., Marcel Dekker, Inc., New York, 1978 ,
  • an antibody of the invention can be administered orally, for example in an inert diluent or an assimilable edible carrier.
  • the antibody (and other ingredients if desired) may also be enclosed in a hard or soft gelatin capsule, compressed into tablets or added directly to the diet.
  • the antibodies may be mixed with excipients and used in the form of swallowable tablets, buccal tablets, capsules, elixirs, suspensions, syrups and the like. If an antibody according to the invention is to be administered by a route other than the parenteral route, it may be necessary to choose a coating of a material which prevents its inactivation.
  • the antibodies of the invention are preferably capable of neutralizing, both in vitro and in vivo, the activity of oligomers of the invention or derivatives thereof to which they bind.
  • the antibodies can therefore inhibit activity Oligomers according to the invention or derivatives thereof are used, for.
  • the subject matter of the invention is a method for inhibiting the activity of oligomers or derivatives thereof according to the invention, wherein an antibody according to the invention is allowed to act on an oligomer or derivative thereof in such a way that the activity of the oligomer or derivative thereof is inhibited.
  • another aspect of the present invention relates to a method of inhibiting the activity of oligomers or derivatives thereof of the invention in a subject afflicted with a disease involving amyloid ⁇ -protein and, in particular, the activity of the oligomer or derivative thereof of the invention is.
  • This method involves the administration of at least one antibody of the invention to the subject for the purpose of inhibiting the activity of the oligomer or derivative thereof to which or which the antibody binds.
  • the individual is preferably a human.
  • An antibody of the invention may be administered to a human subject for therapeutic purposes.
  • an antibody of the invention may be administered to a non-human mammal for veterinary purposes or as part of an animal model for a particular disease. Such animal models may be useful to assess the therapeutic efficacy of antibodies of the invention (e.g., to test dosages and timing of administration).
  • oligomers or derivatives thereof according to the invention play a role
  • diseases in whose formation and / or course an oligomer or derivative thereof according to the invention is involved By this is meant in particular those diseases in which oligomers or derivatives thereof according to the invention are demonstrably or presumably responsible for the pathophysiology of the disease or constitute a factor contributing to the development and / or course of the disease. Accordingly these include those diseases in which the inhibition of the activity of oligomers or derivatives thereof according to the invention is able to alleviate symptoms and / or progression of the disease.
  • the antibodies of the invention may be administered together with one or more additional therapeutic agents useful in the treatment of the diseases described above.
  • compositions of the present invention will generally contain a therapeutically effective amount or a prophylactically effective amount of at least one antibody of the invention.
  • dosage plans can be selected and adjusted. For example, one can administer a single dose, several separate doses over time or administer an increasing or decreasing dosage depending on the requirements of the therapeutic situation. It is particularly advantageous to formulate parenteral compositions in unit dosage form to facilitate administration and to ensure uniformity of dosage.
  • the determination is made immunologically. In principle, this can be done with any analytical or diagnostic test method in which antibodies are used. These include agglutination and precipitation techniques, immunoassays, immunohistochemical methods, and immunoblot techniques, e.g. Western blotting or dot blotting. Also in vivo methods include, for example, imaging methods.
  • immunoassays Both competitive immunoassays, i. Antigen and labeled antigen (tracer) compete for antibody binding, as well as sandwich immunoassays, i. the binding of specific antibodies to the antigen is detected with a second, mostly labeled antibody.
  • sandwich immunoassays i. the binding of specific antibodies to the antigen is detected with a second, mostly labeled antibody.
  • assays can be both homogeneous, i. without a solid and liquid phase separation, as well as being heterogeneous, i. bound labels are separated from unbound ones, for example via solid phase bound antibodies.
  • the different heterogeneous and homogeneous immunoassay formats can be assigned to specific classes depending on the labeling and measuring method, for example RIAs (radioimmunoassays), ELISA (enzyme linked immunosorbent assay), FIA (fluorescence immunoassay), LIA (luminescence immunoassay), TRFIA (temporally resolved FIA), IMAC (immune activation), EMIT (enzyme multiplied immune test), TIA (turbidimetric immunoassay), I-PCR (immuno-PCR).
  • RIAs radioimmunoassays
  • ELISA enzyme linked immunosorbent assay
  • FIA fluorescence immunoassay
  • LIA luminescence immunoassay
  • TRFIA temporary FIA
  • IMAC immunoactivation
  • EMIT enzyme multiplied immune test
  • TIA turbidimetric immunoassay
  • I-PCR immuno-PCR
  • oligomer determination For the oligomer determination according to the invention, competitive immunoassays are preferred. Labeled oligomer (tracer) competes with the sample oligomer to be quantified for binding to the antibody used. From the amount of displaced tracer can be determined using a standard curve, the amount of antigen, that is, the amount of oligomer in the sample.
  • enzymes have proven to be advantageous.
  • systems based on peroxidases especially horseradish peroxidase, may be alkaline Phosphatase and the ß-D-galactosidase can be used.
  • specific substrates are available whose implementation can be followed, for example, photometrically.
  • Suitable substrate systems are based on p-nitrophenyl phosphate (p-NPP), 5-bromo-4-chloro-3-indolyl phosphate / nitroblue tetrazolium (BCIP / NPT), fast red / naphthol AS-TS phosphate for alkaline phosphatase; 2,2-azino-bis- (3-ethylbenzthiazoline-6-sulfonic acid) (ABTS), o-phenylenediamine (OPT), 3,3 ', 5,5'-tetramethylbenzidine (TMB), o-dianisidine, 5-aminosalicylic acid , 3-dimethylaminobenzoic acid (DMAB) and 3-methyl-2-benzothiazoline hydrazone (MBTH) for peroxidases; O-nitrophenyl- ⁇ -D-galactoside (o-NPG), p-nitrophenyl- ⁇ -D-galactoside and 4-methylumbeliphenyl- ⁇ -D
  • Tracers used are labeled oligomers. In this sense, to determine a particular oligomer to mark the oligomer to be determined and use as a tracer.
  • the coupling of labels to oligomers for the preparation of tracers can be done in a conventional manner.
  • the above statements on the derivatization of oligomers according to the invention are referred to by analogy.
  • a number of labels suitably modified for conjugation to proteins are available, for example, biotin, avidin, extravidin or streptavidin-conjugated enzymes, maleimide-activated enzymes, and the like.
  • These labels can be reacted directly with the oligomer or, if necessary, with appropriately derivatized oligomer to form a tracer.
  • a streptavidin-peroxidase conjugate this will first require biotinylation of the oligomer.
  • the skilled person suitable methods are known.
  • the antigen-antibody complex can be bound to the carrier for the purpose of separation, for example via an anti-idiotypic antibody coupled to the carrier, eg an antibody directed against rabbit IgG.
  • Carriers in particular microtiter plates coated with appropriate antibodies, are known and in some cases commercially available.
  • kits usually includes several containers for separate arrangement of components. All components may be provided in ready-to-use dilution, as a dilution concentrate or as a dry substance or lyophilizate to dissolve or suspend; any or all of the components may be frozen or stored at ambient temperature until use. Sera are preferably flash-frozen, for example at -20 ° C, so that in these cases an immunoassay prior to use is preferably to be maintained at freezing temperatures.
  • immunoassay Other components attached to the immunoassay are based on the type of immunoassay. As a rule, standard protein, optionally required tracer and control serum are added together with the antiserum. Further, microtiter plates, preferably coated with antibody, may be added to buffers, for example for testing, washing or reaction of the substrate, and the enzyme substrate itself.
  • substances which inhibit the aggregation of the oligomers according to the invention or accelerate their disaggregation are also of interest.
  • Such substances are in particular possible therapeutics for the treatment of the above amyloid- ⁇ -associated diseases, such. B. Alzheimer's disease.
  • This method can also be applied to mixtures of biological origin, e.g. Cell preparation and extracts to produce natural binding partners having affinity for the oligomers of the invention, e.g. Cell surface antigens, especially receptors, and soluble ligands, such as certain proteins and mediators to identify.
  • biological origin e.g. Cell preparation and extracts
  • natural binding partners having affinity for the oligomers of the invention, e.g. Cell surface antigens, especially receptors, and soluble ligands, such as certain proteins and mediators to identify.
  • the present invention also relates to screening methods, ie both primary and secondary screening methods, in which preferably at least one of the methods described below is used. If several methods are used, this can be done with a time delay or simultaneously on one and the same sample or on different samples of a substance to be investigated.
  • FlashPlateR FlashPlateR technology
  • Kits and components for carrying out this assay may be obtained commercially, for example from NENR Life Science Products. This principle is also based on microtiter plates (96 or 384) coated with scintillant substance.
  • the substances or parts of mixtures of substances identifiable by this method as a ligand binding to the oligomer, derivative thereof or at least one oligomer or derivative thereof containing a corresponding composition thereof are as well the subject of the present invention as their use for the manufacture of a medicament for the treatment of amyloid- ⁇ -associated, in particular dementielle illnesses or for the production of a composition for the diagnosis of amyloid-ß-associated, in particular dementielle illnesses.
  • concentrations of oligomers of the invention are expressed in terms of mole of A ⁇ (1-42) monomeric polypeptide.
  • ⁇ -amyloid (1-42) protein corresponds to the term amyloid ⁇ (1-42) protein.
  • proteins (polypeptides) used are of human origin.
  • Example 1a 60 ⁇ l of the stock solution from Example 1a are admixed with 690 ⁇ l PBS buffer (20 mM sodium phosphate, 140 mM NaCl, pH 7.4) and adjusted to a content of 0.2% with 75 ⁇ l 2% sodium dodecyl sulfate (SDS) solution. SDS set. It is then incubated for 5 hours at 37 ° C and centrifuged for 10 min at 10,000 g. This A ⁇ (1-42) oligomer A preparation (about 400 ⁇ M A ⁇ (1-42)) can be stored at -20 ° C.
  • PBS buffer 20 mM sodium phosphate, 140 mM NaCl, pH 7.4
  • SDS sodium dodecyl sulfate
  • rat A ⁇ (1-42) oligomer A preparation (about 400 ⁇ M rat A ⁇ (1-42)) can be stored at -20 ° C.
  • Example 1 a 60 .mu.l of the stock solution from Example 1 a are mixed with 690 ul PBS buffer (20 mM sodium phosphate, 140 mM NaCl, pH 7.4) and adjusted to a content of 0.5% lauric acid with 75 ul 5% lauric acid solution , It is then incubated for 5 hours at 37 ° C and centrifuged for 10 min at 10,000 g.
  • This A ⁇ (1-42) oligomer A preparation (approximately 400 ⁇ M A ⁇ (1-42)) can be stored at -20 ° C.
  • 60 ⁇ l of the stock solution from example 1a are admixed with 690 ⁇ l PBS buffer (20 mM sodium phosphate, 140 mM NaCl, pH 7.4) and 75 ⁇ l 5% lauroyl sarcosine solution to a content of 0.5% lauroyl sarcosine set. It is then incubated for 5 hours at 37 ° C and centrifuged for 10 min at 10,000 g.
  • This A ⁇ (1-42) oligomer A preparation (approximately 400 ⁇ M A ⁇ (1-42)) can be stored at -20 ° C.
  • ⁇ -amyloid (1-42) protein (abbreviated to A ⁇ (1-42); peptide-synthetic material, lyophilizate, Bachem, Germany) are taken up in 220 ⁇ l of 10 mM aqueous HCl solution and incubated for 10 minutes at room temperature incubated. Insoluble constituents are centrifuged off at 10,000 g, 5 min. The supernatant (1 mM A ⁇ (1-42)) contains the A ⁇ (1-42) protein and is processed as follows:
  • hA ⁇ (1-42) oligomer A preparation 100 ⁇ M can be stored at -20 ° C.
  • a ⁇ (1-42) protein (abbreviated to A ⁇ (1-42), peptide-synthetic material, lyophilizate, Bachem, Germany) are dissolved in 44 ⁇ l of 1% SDS / H 2 O (5 mM A ⁇ (1-42)). 5 ⁇ l of the solution are mixed with 40 ⁇ l PBS and 5 ⁇ l 2% SDS and incubated for 16 h at 37 ° C. Insoluble constituents are centrifuged off for 5 minutes at 10,000 g. The resulting A ⁇ (1-42) oligomer A preparation (500 ⁇ M A ⁇ (1-42)) can be stored at -20 ° C.
  • rat ⁇ -amyloid (1-42) protein (abbreviated to rat A ⁇ (1-42); peptide-synthetic material, lyophilizate, Bachem, Germany) are dissolved in 44 ⁇ l of 1% SDS / H 2 O ( 5 mM rat A ⁇ (1-42)). 5 ⁇ l of the solution are mixed with 40 ⁇ l PBS and 5 ⁇ l 2% SDS and incubated for 16 h at 37 ° C. Insoluble constituents are centrifuged off for 5 minutes at 10,000 g. The rat A ⁇ (1-42) oligomer A preparation (500 ⁇ M rat A ⁇ (1-42)) thus obtained can be stored at -20 ° C.
  • rat A ⁇ (1-42) protein abbreviated to rat A ⁇ (1-42); peptide-synthetic material, lyophilizate, Bachem, Germany
  • 5 ⁇ l of the solution are mixed with 40 ⁇ l PBS and 5 ⁇ l 2% SDS and incubated for 16 h at 37 °
  • An A ⁇ (1-42) oligomer A solution obtained according to Example 2a is diluted with 2.475 ml of water (0.05% SDS content, 0.1 mM A ⁇ (1-42)) and incubated at 37 ° C. for 20 hours , Aliquots of this A ⁇ (1-42) oligomer B preparation can be frozen at -80 ° C and stored for further study.
  • a rat A ⁇ (1-42) oligomer A solution obtained according to Example 2b is diluted with 2.475 ml of water (0.05% SDS content, 0.1 mM rat A ⁇ (1-42)) and for 20 hours Incubated at 37 ° C. Aliquots of this rat A ⁇ (1-42) oligomer B preparation can be frozen at -80 ° C and stored for further study.
  • An A ⁇ (1-42) oligomer A solution obtained according to Example 2c is diluted with 2.475 ml of water (0.125% lauric acid content, 0.1 mM A ⁇ (1-42)) and incubated at 37 ° C. for 20 hours. Aliquots of this A ⁇ (1-42) oligomer B preparation can be frozen at -80 ° C and stored for further study.
  • An A ⁇ (1-42) oligomer B preparation prepared in accordance with Example 5a is admixed with 30 ml of PBS buffer containing 0.1% Pluronic® F68 (BASF) and precipitated in the Centriprep YM, 30 KD, Fa Amicon concentrated to 3 ml. Any residues are removed by centrifugation (5 min at 10,000 g). The supernatant is removed. Aliquots of this A ⁇ (1-42) oligomer B preparation can be frozen at -80 ° C and stored for further study.
  • Pluronic® F68 BASF
  • biotin- ⁇ -amyloid (1-42) protein (short: biotin-A ⁇ (1-42), peptide synthetic material, lyophilisate, AnaSpec) are dissolved in 200 ⁇ l 1,1,1,1,3,3 , 3-hexafluoro-2-propanol and incubated for 30 min at 37 ° C in an Eppendorf tube. It is then evaporated to dryness in a vacuum concentrator (Speed Vac). The residue is taken up in 20.5 ⁇ l of DMSO to give a 5 mM biotin-A ⁇ (1-42) strain suspension. This can be stored at -20 ° C.
  • fluorescein- ⁇ -amyloid (1-42) protein short: fluorescein A ⁇ (1-42), peptide synthetic material, lyophilisate, AnaSpec
  • fluorescein A ⁇ 1-42
  • peptide synthetic material lyophilisate, AnaSpec
  • a vacuum concentrator Speed Vac
  • the residue is taken up with 20.5 ⁇ l of DMSO to give a 5 mM fluorescein-A ⁇ (1-42) strain suspension. This can be stored at -20 ° C.
  • a fluorescein A ⁇ (1-42) oligomer A solution obtained according to Example 11 is diluted with 82 ⁇ l of water (0.05% SDS content, 0.1 mM A ⁇ (1-42)) and at 37 ° for 16 hours C incubated.
  • the fluorescein A ⁇ (1-42) oligomer B preparation can be frozen at -80 ° C and stored for further studies ( Fig. 4 ).
  • the evaluation reveals that the A ⁇ (1-42) oligomer B preparation is characterized by a major peak in the molecular weight region of about 50 kDa Having protein fraction. As under denaturing conditions in SDS-PAGE, this protein fraction differs significantly from the monomeric A ⁇ (1-42) protein characterized by a major peak in the molecular weight region of about 16 kDa.
  • the evaluation reveals that the A ⁇ (1-42) oligomer B preparation with reduced SDS content has a protein fraction characterized by a major peak in the molecular weight range of about 100 kDa.
  • the A ⁇ (1-42) oligomer B-CL preparation with reduced SDS content has a protein fraction characterized by a major peak in the molecular weight region of about 60 kDa.
  • the detergent contained in the preparations is neutralized by the nonionic detergent Triton X-100.
  • 1 .mu.l 4% Triton X-100
  • 10 .mu.l are pipetted to 10 .mu.l of the preparation from Example 5a and incubated for 5 min at room temperature. Thereafter, 10 .mu.l are added with the same volume of native sample buffer (4 ml of 1M Tris, pH 6.8, 8 ml of glycerol, 1 ml bromophenol blue in 50 ml of H 2 O and electrophoresis (running buffer: 7.5 g of tris, 36 g of glycine to 2.5 l of H 2 O).
  • molecular weights can also be assigned to the oligomers according to the invention, in particular to oligomers B, also in native molecular weight analysis methods such as gel permeation chromatography (see Example 17) or native gel electrophoresis (see Example 18).
  • the A ⁇ (1-42) oligomers B obtained according to Example 6b are tested for stability in PBS buffer under the following conditions.
  • the A ⁇ (1-42) oligomers B obtained according to Example 6b are diluted to 0.5 mg / ml with PBS buffer and incubated for 24 hours or 96 hours at room temperature or at 37 ° C. Subsequently, the band pattern was analyzed in an SDS-PAGE. The band pattern is identical in all samples.
  • Aliquots of the A ⁇ (1-42) oligomer B preparation obtained according to Example 6b are diluted to 0.5 mg / ml with buffer (20 mM Na phosphate, 140 mM NaCl, pH 7.4) and incubated with the following conditions 1/50 of the weight of the in Fig. 9 protease solutions incubated for 20 h at 37 ° C and pH 7.4. 1 ⁇ g aliquots of the batches are then analyzed in an SDS-PAGE ( Fig. 9 ).
  • a ⁇ (1-42) oligomers B have high plasma stability.
  • the biological half-life in the plasma is therefore in the range of about 8 hours or longer.
  • biotin A ⁇ (1-42) Binding of biotin A ⁇ (1-42) oligomers with molecular weights of 17 kDa and 22 kDa [biotin A ⁇ (1-42) oligomers A] and of 42 kDa and 52 kDa [biotin A ⁇ (1-42) - Oligomers B] to the surface of human neuronal cells
  • the binding of human ⁇ -amyloid (1-42) protein and the two A ⁇ (1-42) oligomer A and A ⁇ (1-42) oligomer B preparations to the human neuroblastoma cell line IMR-32 is assayed by FACScan (Beckton Dickinson).
  • a suspension of IMR-32 cells (1.5 x 10 6 cells / 0.1 ml PBS) is probed with biotin-labeled, human ⁇ -amyloid (1-42) protein (peptide synthetic material, lyophilisate, AnaSpec) and the Biotin-labeled oligomers A and B containing preparations (Example 8 or 9) for 20 minutes at 37 ° C incubated.
  • the cells are washed with buffer (PBS plus 1% BSA) and incubated with Streptavidin isothiocyanate-coupled fluorescein (Sigma) for 20 minutes at room temperature. After a buffer wash, binding to the surface of IMR-32 cells was analyzed by FACScan. The broken line shows the background fluorescence in the absence of the biotin labeled components. The addition of the individual preparations resulted in a large increase in cell-associated fluorescence and is indicated by the thick line.
  • the binding of the oligomers A ( Fig. 7B ) and B ( Fig. 7C ) to the cell surfaces differs significantly from the binding of the monomeric ⁇ -amyloid (1-42) protein ( Fig. 7A ). The data show specific binding sites for the oligomers on human cell surfaces.
  • a calibration series of the A ⁇ (1-42) oligomer B preparation in PBS in the concentration range of 1.58 ng / ⁇ l-0.005 ng / ⁇ l is initially prepared.
  • a homogenate from a control brain of an untreated rat is carried and similarly a calibration series of the A ⁇ (1-42) oligomer B preparation is prepared in this brain homogenate. Thereafter, the homogenates are centrifuged for 1 h at 100,000 g in the ultracentrifuge and the supernatants used for the subsequent analyzes.
  • the content of A ⁇ (1-42) oligomer B in the positive control can first be determined quantitatively and then also in the brain sample of treated rats as follows determine.
  • rats While no A ⁇ (1-42) (0.01 nmol / g) is detectable in the brain extracts of untreated rats, rats were approximately 0.4 nmol in the 15 min after treatment by comparing the staining intensity with the corresponding concentrations of the positive control / g A ⁇ (1-42) and in the 120 min after treatment killed rats according to the same method still about 0.2 nmol / g detectable. This results in a mean biological half-life of about 105 min for the exogenously applied A ⁇ (1-42) oligomers B.
  • Anti A ⁇ (1-42) reactive bands occur only in the range 38/48 kDa, which corresponds to the apparent molecular weight of the A ⁇ (1-42) oligomers B, ie the oligomeric structure remains in vivo application even after 2 hours receive.
  • the same concentrations in the brains of the 15-min rats (0.4 nmol / g) and the 120-min rats (0.2 nmol / g) can be compared by comparing the staining intensities with corresponding intensely stained bands of A ⁇ (1-42 ) Oligomers B in the positive control as in the dot blot method.
  • the preparation and cultivation of murine cortical neurons is carried out as a mixed culture with glial cells based on the literature ( Choi et al. (1987) J. Neurosci. 7, 357-368 ). In embryos, on 14.-15. Development Day the cortices of the meninges and deeper brain areas mechanically freed. The cells are separated by incubation in a 0.05% trypsin solution at 37 ° C for 5-7 minutes followed by repeated pipetting through a reduced-aperture Pasteur pipette.
  • the toxic effect of A ⁇ (1-42) oligomers B is examined.
  • the cells are incubated for 15 minutes in brain cell buffer (120 mM NaCl, 5.4 mM KCl, 1.8 mM CaCl 2 , 15 mM glucose, 25 mM HEPES, pH 7.2).
  • Control cells 1 are incubated at the same time with 300 ⁇ M L-glutamate in brain cell buffer.
  • the stock solution of A ⁇ oligomers is diluted to various final concentrations with serum-free medium (Minimum Essential Medium with 0.8 mM glutamine, 20 mM glucose, 26 mM NaHCO 3 ) and incubated for 24 h.
  • control cells 1 treated with L-glutamate are incubated in serum-free medium in parallel.
  • Another group of cells (control cells 2) is treated only with brain cell buffer and serum-free medium.
  • the cell culture supernatants are removed, the remaining cells are destroyed by incubation in distilled water for 20 minutes, and the activity of the enzyme lactate dehydrogenase (LDH) in both solutions is determined enzymatically.
  • LDH lactate dehydrogenase
  • control cells 1 Of the Mean value in the glutamate-treated cells (control cells 1) is equated with 100% neuronal death, the mean of the cells treated with neither L-glutamate nor A ⁇ oligomers (control cells 2), with 0% neuronal death and the values of converted accordingly with Aß oligomers treated cells.
  • the mean value of the neurotoxicity of all determinations at the respective concentrations used shows a marked toxic effect of the A ⁇ (1-42) oligomers with molecular weights of 38 kDa and 48 kDa [A ⁇ (1-42) oligomer B], cf. Fig. 8 ,
  • the adjuvant is mixed with a solution of the antigen in the ratio of 2: 1 until a stable emulsion is obtained.
  • the emulsion is injected and forms a depot from which the antigen is released continuously.
  • the antisera are obtained from the rabbit blood by standing at room temperature and then centrifuging at room temperature.
  • the serum thus obtained is called serum (a1).
  • a ⁇ (20-42) oligomer B preparation from Example 15a of LPH are coupled with glutaric dialdehyde under standard conditions and 2 additional rabbits are immunized according to the standard protocol with this conjugated A ⁇ (20-42) oligomer B: 1 day
  • the antisera are obtained from the rabbit blood by standing at room temperature and then centrifuging at room temperature.
  • the serum thus obtained is called serum (a2).
  • the antisera are obtained from the rabbit blood by standing at room temperature and then centrifuging at room temperature.
  • the serum thus obtained is called serum (b1).
  • a ⁇ (12-42) oligomer B preparation from Example 15b are coupled to LPH with glutaric dialdehyde under standard conditions and 2 additional rabbits are immunized according to the standard protocol with this conjugated A ⁇ (12-42) oligomer B: 1 day
  • the antisera are obtained from the rabbit blood by standing at room temperature and then centrifuging at room temperature.
  • the serum thus obtained is called serum (b2).
  • Example 14a 2 rabbits are immunized according to the standard protocol with unconjugated A ⁇ (1-42) oligomer B-CL preparation of Example 14a: 1 day Initial immunization and withdrawal of the preimmune serum 7th day 1. Boost 14th day 2. boost 28th day 3. Boost and bleeding 35th day blood collection
  • the antisera are obtained from the rabbit blood by standing at room temperature and then centrifuging at room temperature.
  • the serum thus obtained is called serum (c1).
  • the antisera are obtained from the rabbit blood by standing at room temperature and then centrifuging at room temperature.
  • the serum thus obtained is called serum (d1).
  • a ⁇ (1-42) oligomer B preparation from Example 6b are coupled to LPH, with glutaric dialdehyde under standard conditions and 2 additional rabbits are immunized according to the standard protocol with this conjugated A ⁇ (1-42) oligomer B preparation: 1 day Initial immunization and withdrawal of the preimmune serum 7th day 1. Boost 14th day 2. boost 28th day 3. Boost and bleeding 35th day blood collection
  • the antisera are obtained from the rabbit blood by standing at room temperature and then centrifuging at room temperature.
  • the serum thus obtained is called serum (d2).
  • the numbers indicate the minimum amount of antigen visible in [pmol; except for APP in each case based on monomer] (detection limit).
  • the antibodies directed against these oligomers are comparable in strength to other forms such as fibrils, APP, and monomer, as with the A ⁇ (1-42) oligomers B (see Row 1) ) cross-react.
  • These antibodies show an immune response comparable to mMAb 6E10 (Signet) and do not bind to oligomer-specific structures.
  • mice were immunized with A ⁇ (1-42) oligomers from Example 6b and monoclonal antibodies were established in a manner known per se. Two out of ten Hybrdidoma secrete monoclonal antibodies whose binding profiles are similar to those of the antiserum (a1), especially with respect to the reactivities tested above.
  • a ⁇ (1-42) solution in 0.1% NH 4 OH are diluted to 0.5 mg / ml with 300 ⁇ l buffer (20 mM Na phosphate, 140 mM NaCl, pH 7.4) and 0, 1 M HCL adjusted to pH 7.4 (100 ⁇ M A ⁇ (1-42)).
  • the sample is incubated for 24 h at 37 ° C and then centrifuged for 10 min at 10,000 g.
  • the protein residue obtained is resuspended with 400 ⁇ l of buffer (20 mM Na phosphate, 140 mM NaCl, pH 7.4).
  • the A ⁇ (1-42) fibril preparation thus obtained can be stored at -20 ° C and used for further studies.
  • FIG. 14 shows that the washing in of A ⁇ (1-42) oligomers suppresses the long-term potentiation in the hippocampus, especially in the "maintenance phase". Accordingly, the A ⁇ (1-42) oligomers B-CL have an influence on the information storage of nerve cells (cellular memory).
  • the binding of rat A ⁇ (1-42) oligomers B from Example 5b to primary rat hippocampal neurons was examined.
  • the hippocampal neurons were cultured in neurobasal medium supplemented with B27 on poly-L-lysine coated coverslips and used on day 14 of culture.
  • the binding of the oligomers to the cell membrane of the neurons was carried out by adding 200 nM (total monomeric A ⁇ concentration) oligomers in fresh culture medium and incubating for 15 min. at 37 ° C. After removal of the A ⁇ -containing medium was washed twice with medium and the cells then fixed in 3.7% formaldehyde. After further washing of the cells, nonspecific binding sites were blocked with 10% normal donkey serum in PBS buffer for 90 min at room temperature.
  • the 1st antibody 6E10 (from mouse) was applied at a dilution of 1: 2000 for 2 h at room temperature.
  • the cells were washed again and incubated with the second antibody (from donkey), which is directed against mouse and to which the fluorescent dye Cy3 is coupled, for 2 h at room temperature.
  • the coverslips with the neurons were fixed on a microscope slide with mounting medium.
  • the hippocampal neurons with bound A ⁇ oligomers were displayed in a fluorescence microscope.
  • an approach was used in which the 1st antibody 6E10 was omitted. This control thus shows the non-specific fluorescence, which is not based on A ⁇ .
  • Fig. 15a As can be seen, the oligomers bind to the cell surface of the neurons in a punctured fashion. In contrast, the control without the first antibody 6E10 shows only a slight unspecific fluorescence by binding of the second antibody to the neurons ( Fig. 15b ).

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Families Citing this family (89)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2002003911A2 (fr) * 2000-07-07 2002-01-17 Lars Lannfelt Prevention et traitement de la maladie d'alzheimer
DE10259382A1 (de) * 2002-12-18 2004-07-01 Abbott Gmbh & Co. Kg 3-Substituierte 3,4-Dihydro-thieno[2,3-d]pyrimidin-4-on-Derivate, ihre Herstellung und Verwendung
DE10303974A1 (de) * 2003-01-31 2004-08-05 Abbott Gmbh & Co. Kg Amyloid-β(1-42)-Oligomere, Verfahren zu deren Herstellung und deren Verwendung
US7732162B2 (en) 2003-05-05 2010-06-08 Probiodrug Ag Inhibitors of glutaminyl cyclase for treating neurodegenerative diseases
US8250823B2 (en) 2003-08-26 2012-08-28 Ejot Gmbh & Co. Kg Dowels and methods for the assembly of insulating panels
SE0401601D0 (sv) * 2004-06-21 2004-06-21 Bioarctic Neuroscience Ab Protofibril specific antibodies and uses thereof
SG190665A1 (en) 2004-07-30 2013-06-28 Rinat Neuroscience Corp Antibodies directed against amyloid-beta peptide and methods using same
EP1787998A4 (fr) * 2004-08-11 2008-08-27 Mitsubishi Chem Corp Anticorps et utilisation s'y rapportant
EP1861422B1 (fr) * 2005-03-05 2010-02-24 Abbott GmbH & Co. KG Methode de criblage, procede servant a purifier des a-beta oligomeres non diffusibles, anticorps selectifs contre les dits a-beta oligomeres non diffusibles et procede servant a preparer ces anticorps
TW200700432A (en) * 2005-03-05 2007-01-01 Abbott Gmbh & Co Kg Screening method, process for purifying of non-diffusible a β oligomers, selective antibodies against said non-diffusible a β oligomers and a process for manufacturing of said antibodies
DE102005014936A1 (de) 2005-03-24 2006-12-14 Abbott Gmbh & Co. Kg Substituierte Oxindol-Derivate, diese enthaltende Arzneimittel und deren Verwendung
MY148086A (en) 2005-04-29 2013-02-28 Rinat Neuroscience Corp Antibodies directed against amyloid-beta peptide and methods using same
TW200726774A (en) * 2005-06-30 2007-07-16 Merck & Co Inc Composition and method for producing stable amyloid beta oligomers
JP2009510002A (ja) 2005-09-30 2009-03-12 アボット ゲゼルシャフト ミット ベシュレンクテル ハフツング ウント コンパニー コマンディトゲゼルシャフト 反発誘導分子(rgm)タンパク質ファミリーのタンパク質の結合ドメイン、及びその機能的断片、及びそれらの使用
PL2289909T3 (pl) 2005-11-30 2015-04-30 Abbvie Inc Sposób przeszukiwania, proces oczyszczania niedyfundujących oligomerów Abeta, selektywne przeciwciała przeciw niedyfundującym oligomerom Abeta i sposób wytwarzania tych przeciwciał
JP2009518010A (ja) * 2005-11-30 2009-05-07 アボット・ラボラトリーズ ヒトβアミロイドタンパク質の組み換え形態の調製方法及びこれらのタンパク質の使用
CN102898519B (zh) * 2005-11-30 2015-10-28 Abbvie公司 抗淀粉样β蛋白的单克隆抗体及其用途
SI2289909T1 (sl) * 2005-11-30 2015-03-31 Abbvie Inc. Presejalni postopek, postopek za čiščenje nedifuzibilnih Abeta-oligomerov, selektivna protitelesa proti nedifuzibilnim Abeta-oligomerom in postopek za izdelavo protiteles
AU2013200177B2 (en) * 2005-11-30 2014-10-02 Abbvie Deutschland Gmbh & Co Kg Monoclonal antibodies against amyloid beta protein and uses thereof
RS52004B (en) * 2005-12-12 2012-04-30 F. Hoffmann-La Roche Ag ANTIBODIES AGAINST AMYLOID BETA WITH GLYCOSILATION IN THE VARIABLE REGION
KR101505201B1 (ko) 2005-12-12 2015-03-24 에이씨 이뮨 에스.에이. 치료적 특성을 갖는 베타 1-42 특이적인 단일클론성 항체
EP2325209A3 (fr) * 2006-03-23 2011-08-03 BioArtic Neuroscience AB Anticorps améliorés sélectifs de protofibrilles et leur utilisation
CL2007002070A1 (es) * 2006-07-14 2008-02-08 Ac Immune S A Genentech Inc Anticuerpo quimerico o humanizado, o fragmentos de ellos, que se adhieren especificamente a por lo menos un epitopo en la proteina beta-amiloide; molecula de acido nucleico que lo codifica; composicion que lo comprende; su uso para tratar enfermedade
ATE426174T1 (de) * 2006-07-28 2009-04-15 Vista Ventures Gmbh Verfahren zum nachweis der amyloid-beta oligomere in kírperflussigkeiten
US8188046B2 (en) 2006-10-16 2012-05-29 University Of South Florida Amyloid beta peptides and methods of use
US8455626B2 (en) * 2006-11-30 2013-06-04 Abbott Laboratories Aβ conformer selective anti-aβ globulomer monoclonal antibodies
AU2008204335B2 (en) 2007-01-11 2013-06-13 Michael Bacher Diagnosis and treatment of Alzheimer's and other neurodementing diseases
EP2125015A1 (fr) * 2007-02-27 2009-12-02 Abbott GmbH & Co. KG Méthode de traitement d'amyloïdoses
US20100311767A1 (en) * 2007-02-27 2010-12-09 Abbott Gmbh & Co. Kg Method for the treatment of amyloidoses
ZA200905537B (en) 2007-03-01 2010-10-27 Probiodrug Ag New use of glutaminyl cyclase inhibitors
US7618944B2 (en) * 2007-03-01 2009-11-17 Intezyne Technologies, Inc. Encapsulated amyloid-beta peptides
EP2142514B1 (fr) 2007-04-18 2014-12-24 Probiodrug AG Dérivés de thio-urée utilisés comme inhibiteurs de la glutaminyl cyclase
US8613923B2 (en) 2007-06-12 2013-12-24 Ac Immune S.A. Monoclonal antibody
EP2574345A1 (fr) * 2007-06-12 2013-04-03 AC Immune S.A. Anticorps humanisés à amyloïde bêta
NZ601843A (en) * 2007-06-12 2014-01-31 Ac Immune Sa Monoclonal anti beta amyloid antibody
US8048420B2 (en) * 2007-06-12 2011-11-01 Ac Immune S.A. Monoclonal antibody
EP2650308A3 (fr) * 2007-10-05 2014-11-12 Genentech, Inc. Utilisation d'anticorps anti-beta amyloide aux maladies oculaires
BRPI0818621A8 (pt) * 2007-10-05 2018-01-30 Ac Immune Sa composição farmacêutica, e, métodos para reduzir a carga da placa e a quantidade de placas na camada de célula de gânglio retinal de um indivíduo, para prevenir, tratar e/ou aliviar os efeitos de uma doença ocular, para diagnosticar uma doença ocular e uma predisposição a uma doença ocular, para monitorar doença ocular, para predizer responsividade de um paciente, e para reter ou diminuir pressão ocular nos olhos de um indivíduo
WO2009048539A2 (fr) 2007-10-05 2009-04-16 Genentech, Inc. Anticorps monoclonal
KR20100115340A (ko) * 2007-10-19 2010-10-27 이무나스 파마 가부시키가이샤 Aβ 올리고머에 특이적으로 결합하는 항체 및 그의 이용
UA103602C2 (ru) * 2007-10-29 2013-11-11 Енсерм (Енстітю Насьональ Де Ля Санте Е Де Ля Решер Медікалє) АНТИТЕЛО, СПЕЦИФИЧНОЕ К β-АМИЛОИДНЫМ ПЕПТИДАМ, И ЕГО ПРИМЕНЕНИЕ В КАЧЕСТВЕ ДИАГНОСТИЧЕСКОГО ИЛИ ЛЕКАРСТВЕННОГО СРЕДСТВА
CA2707309A1 (fr) 2007-12-18 2009-06-25 Acumen Pharmaceuticals, Inc. Nouveaux polypeptides du recepteur de l'addl, polynucleotides et cellules hotes pour une production recombinante
EP3121277B1 (fr) 2008-02-08 2018-04-11 Immunas Pharma, Inc. Anticorps pouvant se lier spécifiquement à ab-oligomère et son utilisation
US20090239888A1 (en) * 2008-02-12 2009-09-24 Wisconsin Alumni Research Foundation Methods for Inhibiting Amyloid Precursor Protein and Beta-Amyloid Production and Accumulation
US8962803B2 (en) 2008-02-29 2015-02-24 AbbVie Deutschland GmbH & Co. KG Antibodies against the RGM A protein and uses thereof
CN102065881B (zh) 2008-04-14 2014-03-12 埃尔奇诺瓦公司 稳定的淀粉样beta单体和寡聚体
WO2010011947A2 (fr) * 2008-07-25 2010-01-28 Abbott Laboratories Analogues du peptide ss-amyloïde, oligomères de celui-ci, procédés de préparation et compositions comprenant lesdits analogues ou oligomères, et leurs utilisations
US20100173828A1 (en) * 2008-07-25 2010-07-08 Abbott Gmbh & Co. Kg Aß(X - 38 .. 43) oligomers, and processes, compositions, and uses thereof
US9085614B2 (en) 2008-08-01 2015-07-21 Immunas Pharma, Inc. Antibodies that specifically bind to Aβ oligomers and uses thereof
US8283162B2 (en) 2009-03-10 2012-10-09 Abbott Laboratories Antibodies relating to PIVKAII and uses thereof
EP2419447B1 (fr) 2009-04-17 2017-08-23 Immunas Pharma, Inc. Anticorps qui se lient spécifiquement aux oligomères a bêta et leur utilisation
EP2258398A1 (fr) 2009-05-26 2010-12-08 Araclón Biotech, S. L. Conjugués d'albumine-peptide d'amyloide et leurs utilisations
EP2273273A1 (fr) 2009-07-11 2011-01-12 Rheinische Friedrich-Wilhelms-Universität Bonn Inhibiteurs de la nitration de peptides ß amyloïdes et leurs utilisations pour le diagnostic et le traitement de la maladie d'Alzheimer
ES2624835T3 (es) 2009-08-06 2017-07-17 Immunas Pharma, Inc. Anticuerpos que se unen específicamente a los oligómeros A beta y uso de los mismos
WO2011016239A1 (fr) 2009-08-06 2011-02-10 Immunas Pharma, Inc. Anticorps qui se lient spécifiquement à des oligomères bêta a et utilisation de ceux-ci
US8501420B2 (en) 2009-08-31 2013-08-06 Abbott Laboratories Biomarkers for prediction of major adverse cardiac events and uses thereof
ES2548913T3 (es) 2009-09-11 2015-10-21 Probiodrug Ag Derivados heterocíclicos como inhibidores de glutaminil ciclasa
CA2780069C (fr) 2009-12-08 2018-07-17 Abbott Gmbh & Co. Kg Anticorps monoclonaux contre la proteine rgm a destines a etre utilises dans le traitement de la degenerescence de la couche de fibres nerveuses retiniennes
JP6026284B2 (ja) 2010-03-03 2016-11-16 プロビオドルグ エージー グルタミニルシクラーゼの阻害剤
JP5688745B2 (ja) 2010-03-10 2015-03-25 プロビオドルグ エージー グルタミニルシクラーゼ(qc、ec2.3.2.5)の複素環阻害剤
EP2558494B1 (fr) 2010-04-15 2018-05-23 AbbVie Inc. Protéines de liaison à la bêta amyloïde
WO2011131748A2 (fr) 2010-04-21 2011-10-27 Probiodrug Ag Nouveaux inhibiteurs
US9320793B2 (en) * 2010-07-14 2016-04-26 Acumen Pharmaceuticals, Inc. Method for treating a disease associated with soluble, oligomeric species of amyloid beta 1-42
US9120862B2 (en) 2010-07-26 2015-09-01 Abbott Laboratories Antibodies relating to PIVKA-II and uses thereof
NZ606357A (en) 2010-07-30 2015-05-29 Genentech Inc Safe and functional humanized anti beta-amyloid antibody
US9062101B2 (en) 2010-08-14 2015-06-23 AbbVie Deutschland GmbH & Co. KG Amyloid-beta binding proteins
WO2012123563A1 (fr) 2011-03-16 2012-09-20 Probiodrug Ag Dérivés de benzimidazole en tant qu'inhibiteurs de la glutaminyl cyclase
US8906382B2 (en) * 2011-07-19 2014-12-09 New York University Method for treating amyloid disease
US9926353B2 (en) 2011-07-19 2018-03-27 New York University Immunotherapeutic modulation of amyloidogenic disease using non-fibrillogenic, non-amyloidogenic polymerized proteins and peptides
MY194587A (en) 2012-01-27 2022-12-05 Abbvie Inc Composition and method for the diagnosis and treatment of diseases associated with neurite degeneration
JP2015511014A (ja) * 2012-03-13 2015-04-13 ヤンセン アルツハイマー イミュノセラピー アルツハイマー病の診断、予後および監視におけるオリゴマー型Aβ
CN104380111B (zh) * 2012-04-05 2017-08-29 于利希研究中心有限公司 包含多价结合淀粉样β蛋白的D‑肽的聚合物及其应用
DK3498692T3 (da) 2014-01-31 2022-05-16 Cognition Therapeutics Inc Isoindolin-sammensætninger og fremgangsmåder til behandling af neurodegenerativ sygdom og makulær degeneration
MX2017000378A (es) 2014-07-10 2017-08-25 Bioarctic Neuroscience Ab ANTICUERPOS DE UNION A PROTOFIBRILLAS BETA AMILOIDE (Aß) MEJORADOS.
US20180050084A1 (en) * 2015-02-27 2018-02-22 Board Of Regents, The University Of Texas System Polypeptide therapeutics and uses thereof
IL302486A (en) 2015-06-24 2023-06-01 Hoffmann La Roche Antibodies against the transnephrine receptor with adapted affinity
JP6832283B2 (ja) 2015-09-29 2021-02-24 浜松ホトニクス株式会社 アミロイドβオリゴマーの検出方法、アミロイドβオリゴマー検出装置及びアミロイドβオリゴマー検出プログラム
AR106189A1 (es) 2015-10-02 2017-12-20 Hoffmann La Roche ANTICUERPOS BIESPECÍFICOS CONTRA EL A-b HUMANO Y EL RECEPTOR DE TRANSFERRINA HUMANO Y MÉTODOS DE USO
MX2018003822A (es) 2015-10-02 2018-06-22 Hoffmann La Roche Anticuerpos biespecificos contra el cd20 humano y el receptor de transferrina humano y metodos de uso.
EP3461819B1 (fr) 2017-09-29 2020-05-27 Probiodrug AG Inhibiteurs de la glutaminyl-cyclase
DE102017130356A1 (de) * 2017-12-18 2019-06-19 Georg-August-Universität Göttingen Stiftung Öffentlichen Rechts, Universitätsmedizin Verfahren zur Auftrennung verschiedener Abeta-Peptide durch Gelelektrophorese
US11905336B2 (en) 2018-09-10 2024-02-20 Lung Therapeutics, Inc. Modified peptide fragments of CAV-1 protein and the use thereof in the treatment of fibrosis
CN110412294B9 (zh) * 2019-08-07 2023-05-26 深圳市新产业生物医学工程股份有限公司 蛋白稳定液、蛋白校准品、试剂盒及检测蛋白校准品稳定性的方法
CN113308439B (zh) * 2020-11-06 2023-05-05 华中科技大学 分泌人淀粉样蛋白-β单克隆抗体的杂交瘤细胞株及其应用
TW202300517A (zh) 2021-03-12 2023-01-01 美商美國禮來大藥廠 抗類澱粉β抗體及其用途
WO2022251048A1 (fr) 2021-05-24 2022-12-01 Eli Lilly And Company Anticorps anti-amyloïde bêta et leurs utilisations
WO2023107830A1 (fr) * 2021-12-06 2023-06-15 The Board Of Trustees Of The Leland Stanford Junior University Compositions d'oligomères amyloïdes
WO2023149801A1 (fr) * 2022-02-03 2023-08-10 Erasmus University Medical Center Rotterdam Procédé de préparation d'un anticorps spécifique à une conformation
CN117024554A (zh) * 2023-05-30 2023-11-10 中国人民解放军空军军医大学 一种Aβ1-42寡聚体存储液的制备方法及其应用

Citations (41)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4399216A (en) 1980-02-25 1983-08-16 The Trustees Of Columbia University Processes for inserting DNA into eucaryotic cells and for producing proteinaceous materials
US4510245A (en) 1982-11-18 1985-04-09 Chiron Corporation Adenovirus promoter system
US4634665A (en) 1980-02-25 1987-01-06 The Trustees Of Columbia University In The City Of New York Processes for inserting DNA into eucaryotic cells and for producing proteinaceous materials
US4816397A (en) 1983-03-25 1989-03-28 Celltech, Limited Multichain polypeptides or proteins and processes for their production
EP0368684A1 (fr) 1988-11-11 1990-05-16 Medical Research Council Clonage de séquences d'immunoglobulines de domaines variables.
US4968615A (en) 1985-12-18 1990-11-06 Ciba-Geigy Corporation Deoxyribonucleic acid segment from a virus
EP0436597A1 (fr) 1988-09-02 1991-07-17 Protein Eng Corp Production et selection de proteines de liaison diversifiees de recombinaison.
WO1991017271A1 (fr) 1990-05-01 1991-11-14 Affymax Technologies N.V. Procedes de triage de banques d'adn recombine
WO1992001047A1 (fr) 1990-07-10 1992-01-23 Cambridge Antibody Technology Limited Procede de production de chainon de paires a liaison specifique
WO1992002551A1 (fr) 1990-08-02 1992-02-20 B.R. Centre Limited Procedes de production de proteines presentant une fonction souhaitee
WO1992009690A2 (fr) 1990-12-03 1992-06-11 Genentech, Inc. Methode d'enrichissement pour des variantes de l'hormone de croissance avec des proprietes de liaison modifiees
WO1992020791A1 (fr) 1990-07-10 1992-11-26 Cambridge Antibody Technology Limited Methode de production de chainons de paires de liaison specifique
US5168062A (en) 1985-01-30 1992-12-01 University Of Iowa Research Foundation Transfer vectors and microorganisms containing human cytomegalovirus immediate-early promoter-regulatory DNA sequence
US5179017A (en) 1980-02-25 1993-01-12 The Trustees Of Columbia University In The City Of New York Processes for inserting DNA into eucaryotic cells and for producing proteinaceous materials
US5223409A (en) 1988-09-02 1993-06-29 Protein Engineering Corp. Directed evolution of novel binding proteins
US5545806A (en) 1990-08-29 1996-08-13 Genpharm International, Inc. Ransgenic non-human animals for producing heterologous antibodies
US5569825A (en) 1990-08-29 1996-10-29 Genpharm International Transgenic non-human animals capable of producing heterologous antibodies of various isotypes
WO1996033735A1 (fr) 1995-04-27 1996-10-31 Abgenix, Inc. Anticorps humains derives d'une xenosouris immunisee
WO1996034096A1 (fr) 1995-04-28 1996-10-31 Abgenix, Inc. Anticorps humains derives de xeno-souris immunisees
WO1997008320A1 (fr) 1995-08-18 1997-03-06 Morphosys Gesellschaft Für Proteinoptimierung Mbh Banques de proteines/(poly)peptides
US5625126A (en) 1990-08-29 1997-04-29 Genpharm International, Inc. Transgenic non-human animals for producing heterologous antibodies
US5633425A (en) 1990-08-29 1997-05-27 Genpharm International, Inc. Transgenic non-human animals capable of producing heterologous antibodies
WO1997029131A1 (fr) 1996-02-09 1997-08-14 Basf Aktiengesellschaft ANTICORPS HUMAINS SE FIXANT AU FACTEUR NECROSANT DES TUMEURS DE TYPE $g(a)
US5661016A (en) 1990-08-29 1997-08-26 Genpharm International Inc. Transgenic non-human animals capable of producing heterologous antibodies of various isotypes
WO1998024893A2 (fr) 1996-12-03 1998-06-11 Abgenix, Inc. MAMMIFERES TRANSGENIQUES POSSEDANT DES LOCI DE GENES D'IMMUNOGLOBULINE D'ORIGINE HUMAINE, DOTES DE REGIONS VH ET Vλ, ET ANTICORPS PRODUITS A PARTIR DE TELS MAMMIFERES
US5770429A (en) 1990-08-29 1998-06-23 Genpharm International, Inc. Transgenic non-human animals capable of producing heterologous antibodies
WO1998031700A1 (fr) 1997-01-21 1998-07-23 The General Hospital Corporation Selection de proteines a l'aide de fusions arn-proteine
US5814318A (en) 1990-08-29 1998-09-29 Genpharm International Inc. Transgenic non-human animals for producing heterologous antibodies
WO1998047343A2 (fr) 1997-04-04 1998-10-29 Biosite Diagnostics, Inc. Bibliotheques polyvalentes et polyclonales
WO1998049286A2 (fr) 1997-05-01 1998-11-05 Board Of Regents, The University Of Texas System Evolution orientee d'enzymes et d'anticorps
US5877397A (en) 1990-08-29 1999-03-02 Genpharm International Inc. Transgenic non-human animals capable of producing heterologous antibodies of various isotypes
US5885793A (en) 1991-12-02 1999-03-23 Medical Research Council Production of anti-self antibodies from antibody segment repertoires and displayed on phage
WO1999036569A1 (fr) 1998-01-20 1999-07-22 The Board Of Trustees Of The University Of Illinois Proteines pour la presentation de la surface d'une cellule de levure et leurs utilisations
US5939598A (en) 1990-01-12 1999-08-17 Abgenix, Inc. Method of making transgenic mice lacking endogenous heavy chains
WO1999045962A1 (fr) 1998-03-13 1999-09-16 Genpharm International, Inc. Animaux transgeniques capables de fabriquer des anticorps heterologues
WO1999053049A1 (fr) 1998-04-15 1999-10-21 Abgenix, Inc. Production d'anticorps humains par des epitopes et formation de profils d'expression genique
WO2000056772A1 (fr) 1999-03-25 2000-09-28 Knoll Gmbh Anticorps humains se liant a l'interleukine-12 humaine et procedes de production de ces derniers
WO2001010900A2 (fr) 1999-08-04 2001-02-15 University Of Southern California PROTEINE D'AMYLOIDE β (ENSEMBLE GLOBULAIRE ET SES UTILISATIONS)
US6218506B1 (en) 1997-02-05 2001-04-17 Northwestern University Amyloid β protein (globular assembly and uses thereof)
WO2003016467A2 (fr) 2001-08-17 2003-02-27 Eli Lilly And Company Utilisation d'anticorps ayant une forte affinite pour le peptide a$g(b) dans le traitement de pathologies et de maladies liees a a$g(b)
WO2003016466A2 (fr) 2001-08-17 2003-02-27 Eli Lilly And Company Anticorps anti-$g(a)$g(b)

Family Cites Families (683)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE2500076C3 (de) 1975-01-02 1982-11-18 SCHURA Blutderivate GmbH & Co KG, 4150 Krefeld Verfahren zur Gewinnung von intravenös-verträglichen Gammaglobulinen
NO812612L (no) 1980-08-06 1982-02-08 Ferring Pharma Ltd Enzym-inhibitorer.
BR8108820A (pt) 1980-09-24 1982-08-24 Cetus Corp Processo e sonda de diagnostico
DE3381518D1 (de) 1982-01-22 1990-06-07 Cetus Corp Verfahren zur charakterisierung von hla und die darin benutzten cdns-testmittel.
US4582788A (en) 1982-01-22 1986-04-15 Cetus Corporation HLA typing method and cDNA probes used therein
ATE37983T1 (de) 1982-04-22 1988-11-15 Ici Plc Mittel mit verzoegerter freigabe.
US4816567A (en) 1983-04-08 1989-03-28 Genentech, Inc. Recombinant immunoglobin preparations
US4526039A (en) 1983-06-23 1985-07-02 The United States Of America As Represented By The Secretary Of Transportation Removable strain gauge fixture and method for measuring accumulated strain in a material
US4683194A (en) 1984-05-29 1987-07-28 Cetus Corporation Method for detection of polymorphic restriction sites and nucleic acid sequences
US5807715A (en) 1984-08-27 1998-09-15 The Board Of Trustees Of The Leland Stanford Junior University Methods and transformed mammalian lymphocyte cells for producing functional antigen-binding protein including chimeric immunoglobulin
US5128326A (en) 1984-12-06 1992-07-07 Biomatrix, Inc. Drug delivery systems based on hyaluronans derivatives thereof and their salts and methods of producing same
US4683202A (en) 1985-03-28 1987-07-28 Cetus Corporation Process for amplifying nucleic acid sequences
EP0590689B2 (fr) 1985-03-30 2006-08-16 KAUFFMAN, Stuart A. Procédé d'obtention d'ADN, ARN, peptides, polypeptides ou protéines, par une technique de recombinaison d'ADN
US6492107B1 (en) 1986-11-20 2002-12-10 Stuart Kauffman Process for obtaining DNA, RNA, peptides, polypeptides, or protein, by recombinant DNA technique
US4666829A (en) 1985-05-15 1987-05-19 University Of California Polypeptide marker for Alzheimer's disease and its use for diagnosis
US4980286A (en) 1985-07-05 1990-12-25 Whitehead Institute For Biomedical Research In vivo introduction and expression of foreign genetic material in epithelial cells
US5618920A (en) 1985-11-01 1997-04-08 Xoma Corporation Modular assembly of antibody genes, antibodies prepared thereby and use
DE3600905A1 (de) 1986-01-15 1987-07-16 Ant Nachrichtentech Verfahren zum dekodieren von binaersignalen sowie viterbi-dekoder und anwendungen
CA1284931C (fr) 1986-03-13 1991-06-18 Henry A. Erlich Procede de detection de variations specifiques de nucleotides et de polymorphismes genetiques dans les acides nucleiques
US5225539A (en) 1986-03-27 1993-07-06 Medical Research Council Recombinant altered antibodies and methods of making altered antibodies
GB8607679D0 (en) 1986-03-27 1986-04-30 Winter G P Recombinant dna product
US5107065A (en) 1986-03-28 1992-04-21 Calgene, Inc. Anti-sense regulation of gene expression in plant cells
CA1338457C (fr) 1986-08-22 1996-07-16 Henry A. Erlich Enzyme thermostable purifiee
US5525339A (en) 1986-08-27 1996-06-11 Dms Pharmaceutical Inc. Isolated components of dense microspheres derived from mammalian brain tissue and antibodies thereto
US5231170A (en) 1986-08-27 1993-07-27 Paul Averback Antibodies to dense microspheres
US4946778A (en) 1987-09-21 1990-08-07 Genex Corporation Single polypeptide chain binding molecules
US5811310A (en) 1986-09-30 1998-09-22 Albert Einstein College Of Medicine Of Yeshiva Univ. The Alz-50 monoclonal antibody and diagnostic assay for alzheimer's disease
JPS63240797A (ja) 1986-10-14 1988-10-06 Shin Etsu Chem Co Ltd モノクローナル抗体、その製法およびそれを含有する診断薬
EP0274826B1 (fr) 1986-11-17 1998-08-12 Scios Inc. Protéine recombinante amyloide d'alzheimer
DE3702789A1 (de) 1987-01-30 1988-08-18 Bayer Ag Vorlaeuferprotein des apc-polypeptids, dafuer codierende dna und diagnostische verwendung der dna und des proteins
DE3883899T3 (de) 1987-03-18 1999-04-22 Sb2, Inc., Danville, Calif. Geänderte antikörper.
JPS63245689A (ja) 1987-03-31 1988-10-12 Suntory Ltd ヒトアミロイド関連蛋白モノクロ−ナル抗体
US5258498A (en) 1987-05-21 1993-11-02 Creative Biomolecules, Inc. Polypeptide linkers for production of biosynthetic proteins
US4880078A (en) 1987-06-29 1989-11-14 Honda Giken Kogyo Kabushiki Kaisha Exhaust muffler
CA1340802C (fr) 1987-08-15 1999-10-26 Yasuyuki Takahashi Proteine precurseur de l'amyloide senile et anticorps specifique pour cette proteine
US5004697A (en) 1987-08-17 1991-04-02 Univ. Of Ca Cationized antibodies for delivery through the blood-brain barrier
US5231000A (en) 1987-10-08 1993-07-27 The Mclean Hospital Antibodies to A4 amyloid peptide
CA1339014C (fr) 1987-10-08 1997-03-25 Ronald E. Majocha Anticorps pour peptide a4-amyloide
WO1989006689A1 (fr) 1988-01-13 1989-07-27 The Mclean Hospital Corporation Constructions genetiques renfermant le gene amyloide cerebral d'alzheimer
WO1989007657A1 (fr) 1988-02-10 1989-08-24 The Children's Medical Center Corporation Precurseurs de proteines amyloides, sondes genetiques, anticorps, et modes d'utilisation
US5134062A (en) 1988-03-22 1992-07-28 Cornell Research Foundation, Inc. Diagnosis of neuronal disorders and screening potential therapeutic agents therefor
US5015570A (en) 1988-05-13 1991-05-14 Molecular Therapeutics, Inc. Molecular diagnosis of Alzheimer Disease
US6287793B1 (en) 1988-08-19 2001-09-11 Elan Pharmaceuticals, Inc. Diagnostic methods for alzheimer's disease
US20040049014A1 (en) 1988-12-28 2004-03-11 Protein Design Labs, Inc. Humanized immunoglobulins
US5530101A (en) 1988-12-28 1996-06-25 Protein Design Labs, Inc. Humanized immunoglobulins
US5231020A (en) 1989-03-30 1993-07-27 Dna Plant Technology Corporation Genetic engineering of novel plant phenotypes
US5262332A (en) 1989-04-05 1993-11-16 Brigham And Women's Hospital Diagnostic method for Alzheimer's disease: examination of non-neural tissue
AU5525090A (en) 1989-04-14 1990-11-16 Research Foundation For Mental Hygiene, Inc. Monoclonal antibody to amyloid peptide
CA2057923A1 (fr) 1989-05-16 1990-11-17 William D. Huse Co-expression de recepteurs heteromeriques
CA2016842A1 (fr) 1989-05-16 1990-11-16 Richard A. Lerner Methode pour puiser dans le repertoire immunologique
CA2016841C (fr) 1989-05-16 1999-09-21 William D. Huse Methode de production de polymeres ayant une activite choisie
US5234814A (en) 1989-06-01 1993-08-10 Du Pont Merck Pharmaceutical Company Diagnostic assay for alzheimer's disease
EP0415801A1 (fr) 1989-07-05 1991-03-06 N.V. Innogenetics S.A. Anticorps monoclonaux contre cellules microglia activées
EP0411974A1 (fr) 1989-07-05 1991-02-06 N.V. Innogenetics S.A. Anticorps monoclonaux contre une antigène d'enchevêtrements neurofibrillaires
AU6430190A (en) 1989-10-10 1991-05-16 Pitman-Moore, Inc. Sustained release composition for macromolecular proteins
WO1991006287A1 (fr) 1989-11-06 1991-05-16 Enzytech, Inc. Microspheres de proteines et leurs procedes d'utilisation
GB8928874D0 (en) 1989-12-21 1990-02-28 Celltech Ltd Humanised antibodies
US5780225A (en) 1990-01-12 1998-07-14 Stratagene Method for generating libaries of antibody genes comprising amplification of diverse antibody DNAs and methods for using these libraries for the production of diverse antigen combining molecules
AU7247191A (en) 1990-01-11 1991-08-05 Molecular Affinities Corporation Production of antibodies using gene libraries
US6075181A (en) 1990-01-12 2000-06-13 Abgenix, Inc. Human antibodies derived from immunized xenomice
AU7121191A (en) 1990-02-26 1991-10-10 Albert Einstein College Of Medicine Of Yeshiva University Diagnostic assay for alzheimer's disease
US5753624A (en) 1990-04-27 1998-05-19 Milkhaus Laboratory, Inc. Materials and methods for treatment of plaquing disease
DE4022247A1 (de) 1990-07-12 1992-01-16 Hoechst Ag Verfahren zur extraktiven abtrennung von 2-alkylthio-5-phenylpyrimidinen aus ihren reaktionsgemischen
US5698426A (en) 1990-09-28 1997-12-16 Ixsys, Incorporated Surface expression libraries of heteromeric receptors
AU1545692A (en) 1991-03-01 1992-10-06 Protein Engineering Corporation Process for the development of binding mini-proteins
CA2108147C (fr) 1991-04-10 2009-01-06 Angray Kang Banques de recepteurs heterodimeriques construites a l'aide de phagemides
ATE221379T1 (de) 1991-05-01 2002-08-15 Jackson H M Found Military Med Verfahren zur behandlung infektiöser respiratorischer erkrankungen
JPH04342883A (ja) 1991-05-17 1992-11-30 Sanden Corp 容量可変型斜板式圧縮機
EP0519596B1 (fr) 1991-05-17 2005-02-23 Merck & Co. Inc. Procédé pour réduire l'immunogénicité des domaines variables d'anticorps
EP0590067A1 (fr) 1991-06-14 1994-04-06 Xoma Corporation Fragments d'anticorps produits par des microbes et leurs conjugues
DE4122599C2 (de) 1991-07-08 1993-11-11 Deutsches Krebsforsch Phagemid zum Screenen von Antikörpern
ES2136092T3 (es) 1991-09-23 1999-11-16 Medical Res Council Procedimientos para la produccion de anticuerpos humanizados.
DE69220503T2 (de) 1991-10-25 1998-02-05 Innogenetics Nv Monoklonale Antikörper gegen das mikrotubulusassoziierte Protein Tau.
DE69227380T3 (de) 1991-11-12 2007-01-11 Prana Biotechnology Ltd., South Melbourne Verfahren zur bestimmung und behandlung von alzheimer-krankheit
US20020009443A1 (en) 1991-12-02 2002-01-24 Vanitha Ramakrishman Inhibitory immunoglobulin polypeptides to human pdgf beta receptor
WO1993011231A1 (fr) 1991-12-06 1993-06-10 MAX-PLANCK-Gesellschaft zur Förderung der Wissenschaften e.V. Outils de diagnostic et de traitement de la maladie d'alzheimer
US7408027B1 (en) 1991-12-06 2008-08-05 Max-Planck-Gesellschaft Zur Forderung Der Wissenchaften Tools for the diagnosis and treatment of Alzheimer's disease
EP0571613B1 (fr) 1991-12-13 2003-09-17 Xoma Corporation Materiels et methodes pour preparer des domaines variables d'anticorps modifies et leurs utilisations therapeutiques
US20010029293A1 (en) 1992-01-27 2001-10-11 Icos Corporation Icam-related protein
US5538845A (en) 1992-02-05 1996-07-23 Athena Neurosciences, Inc. Beta-amyloid peptide production inhibitors and methods for their identification
US5714350A (en) 1992-03-09 1998-02-03 Protein Design Labs, Inc. Increasing antibody affinity by altering glycosylation in the immunoglobulin variable region
US5912015A (en) 1992-03-12 1999-06-15 Alkermes Controlled Therapeutics, Inc. Modulated release from biocompatible polymers
US5733743A (en) 1992-03-24 1998-03-31 Cambridge Antibody Technology Limited Methods for producing members of specific binding pairs
US5912120A (en) 1992-04-09 1999-06-15 The United States Of America As Represented By The Department Of Health And Human Services, Cloning, expression and diagnosis of human cytochrome P450 2C19: the principal determinant of s-mephenytoin metabolism
US5441870A (en) 1992-04-15 1995-08-15 Athena Neurosciences, Inc. Methods for monitoring cellular processing of β-amyloid precursor protein
US5604102A (en) 1992-04-15 1997-02-18 Athena Neurosciences, Inc. Methods of screening for β-amyloid peptide production inhibitors
US5455169A (en) 1992-06-04 1995-10-03 Alzheimer's Institute Of America, Inc. Nucleic acids for diagnosing and modeling Alzheimer's disease
US6610493B1 (en) 1993-06-17 2003-08-26 Brigham And Women's Hospital Screening compounds for the ability to alter the production of amyloid-β peptide
US5837672A (en) 1992-07-10 1998-11-17 Athena Neurosciences, Inc. Methods and compositions for the detection of soluble β-amyloid peptide
US5766846A (en) 1992-07-10 1998-06-16 Athena Neurosciences Methods of screening for compounds which inhibit soluble β-amyloid peptide production
WO1994002602A1 (fr) 1992-07-24 1994-02-03 Cell Genesys, Inc. Production d'anticorps xenogeniques
US5639641A (en) 1992-09-09 1997-06-17 Immunogen Inc. Resurfacing of rodent antibodies
TW258789B (fr) 1992-09-28 1995-10-01 Rohm & Haas
US5605811A (en) 1992-10-26 1997-02-25 Athena Neurosciences, Inc. Methods and compositions for monitoring cellular processing of beta-amyloid precursor protein
US5891623A (en) 1992-11-09 1999-04-06 Consorzio Per Le Biotecnologie Diagnosis and treatment of AIDS onset
ZA938243B (en) 1992-11-12 1995-05-04 Hybritech Inc Altered affinity polypeptides of metal chelate binding antibodies
US6010913A (en) 1992-12-14 2000-01-04 N.V. Innogenetics S.A. Isolated human tau peptide
US5955317A (en) 1993-01-25 1999-09-21 Takeda Chemical Industries, Ltd. Antibodies to β-amyloids or their derivatives and use thereof
EP1308461A3 (fr) 1993-01-25 2004-02-11 Takeda Chemical Industries, Ltd. Anticorps contre des bèta-amyloides ou leurs dérivés, et leurs utilisations
US5934272A (en) 1993-01-29 1999-08-10 Aradigm Corporation Device and method of creating aerosolized mist of respiratory drug
CA2115900A1 (fr) 1993-02-22 1994-08-23 Gerald W. Becker Cribles pharmaceutiques et anticorps
US5840294A (en) 1993-03-29 1998-11-24 Queen's University At Kingston Method for treating amyloidosis
AU698962B2 (en) 1993-09-14 1998-11-12 Epimmune, Inc. Alteration of immune response using pan DR-binding peptides
ATE213507T1 (de) 1993-10-20 2002-03-15 Univ Duke Methode zur bindung von material an das beta- amyloid-peptid
US5565352A (en) 1993-11-24 1996-10-15 Arch Development Corporation Deubiquitinating enzyme: compositions and methods
EP0733070A1 (fr) 1993-12-08 1996-09-25 Genzyme Corporation Procede de generation d'anticorps specifiques
AU1397495A (en) 1993-12-13 1995-07-03 Uab Research Foundation, The Diagnostic tests and reagents for detecting risk of alzheimer's disease and stroke
US6432404B1 (en) 1993-12-23 2002-08-13 Icos Corporation Methods of inhibiting locomotor damage following spinal cord injury with α D-specific antibodies
US6620915B2 (en) 1993-12-23 2003-09-16 Icos Corporation Monoclonal antibodies specific for integrin α-d subunit
US6251395B1 (en) 1993-12-23 2001-06-26 W. Michael Gallatin Methods of inhibiting inflammation at the site of a central nervous system injury with alphaD-specific antibodies
US5877399A (en) 1994-01-27 1999-03-02 Johns Hopkins University Transgenic mice expressing APP-Swedish mutation develop progressive neurologic disease
ES2247204T3 (es) 1994-01-31 2006-03-01 Trustees Of Boston University Bancos de anticuerpos policlonales.
JPH07238096A (ja) 1994-02-25 1995-09-12 S R L:Kk 抗ポリユビキチン・モノクローナル抗体およびポリユビキチンの測定方法
US7473423B2 (en) 1994-04-29 2009-01-06 Mayo Foundation For Medical Education And Research Human IgM antibodies, and diagnostic and therapeutic uses thereof particularly in the central nervous system
US5516637A (en) 1994-06-10 1996-05-14 Dade International Inc. Method involving display of protein binding pairs on the surface of bacterial pili and bacteriophage
US6018021A (en) 1994-10-19 2000-01-25 The Research Foundation Of State University Of New York Human transaldolase: an autoantigen with a function in metabolism
US6114133A (en) 1994-11-14 2000-09-05 Elan Pharmaceuticals, Inc. Methods for aiding in the diagnosis of Alzheimer's disease by measuring amyloid-β peptide (x-≧41)
EP0805678B1 (fr) 1995-01-05 2003-10-29 THE BOARD OF REGENTS acting for and on behalf of THE UNIVERSITY OF MICHIGAN Nanoparticules a modification de surface et leurs procedes de fabrication et d'utilisation
US5786180A (en) 1995-02-14 1998-07-28 Bayer Corporation Monoclonal antibody 369.2B specific for β A4 peptide
JP3663228B2 (ja) 1995-03-14 2005-06-22 株式会社医学生物学研究所 ニューロプシンに対する抗体
US6091001A (en) 1995-03-29 2000-07-18 Abgenix, Inc. Production of antibodies using Cre-mediated site-specific recombination
US6130364A (en) 1995-03-29 2000-10-10 Abgenix, Inc. Production of antibodies using Cre-mediated site-specific recombination
US5705330A (en) 1995-04-14 1998-01-06 Abbott Laboratories Chemiluminescent immunoassay for antibody detection
US6019968A (en) 1995-04-14 2000-02-01 Inhale Therapeutic Systems, Inc. Dispersible antibody compositions and methods for their preparation and use
JP3392627B2 (ja) 1995-04-17 2003-03-31 三洋電機株式会社 2次元映像を3次元映像に変換する方法
WO1996033266A1 (fr) 1995-04-21 1996-10-24 Cell Genesys, Inc. Creation d'importantes deletions d'adn genomique
US5712158A (en) 1995-06-06 1998-01-27 Warner-Lambert Company Cell line for the rapid expression of functional calcium channels
US6717031B2 (en) 1995-06-07 2004-04-06 Kate Dora Games Method for selecting a transgenic mouse model of alzheimer's disease
WO1996040731A1 (fr) 1995-06-07 1996-12-19 Mount Sinai School Of Medicine Of The City University Of New York Proteines modifiees conjuguees a du polyethylene-glycol (peg)
JP3081512B2 (ja) 1995-06-21 2000-08-28 三洋電機株式会社 立体映像装置
JP3767755B2 (ja) 1995-06-23 2006-04-19 エーザイ株式会社 抗jcウイルス抗体
US6127977A (en) 1996-11-08 2000-10-03 Cohen; Nathan Microstrip patch antenna with fractal structure
US5916597A (en) 1995-08-31 1999-06-29 Alkermes Controlled Therapeutics, Inc. Composition and method using solid-phase particles for sustained in vivo release of a biologically active agent
DE69632056T2 (de) 1995-09-14 2004-12-30 The Regents Of The University Of California, Oakland Für natives prp-sc spezifische antikörper
FR2740454B1 (fr) 1995-10-26 1997-11-21 Rhone Poulenc Rorer Sa Peptides capables d'inhiber l'endocytose de l'app et sequences nucleotidiques correspondantes
AUPN649395A0 (en) 1995-11-10 1995-12-07 Ramsay Health Care Pty Ltd A method for diagnosing alzheimer's disease
FR2741881B1 (fr) 1995-12-01 1999-07-30 Centre Nat Rech Scient Nouveaux derives de purine possedant notamment des prorietes anti-proliferatives et leurs applications biologiques
WO1997021807A1 (fr) 1995-12-12 1997-06-19 Kyowa Hakko Kogyo Co., Ltd. Nouveaux adn, nouveaux polypeptides et nouveaux anticorps
JPH09178743A (ja) 1995-12-27 1997-07-11 Oriental Yeast Co Ltd 可溶性appの定量法
ATE219247T1 (de) 1996-01-19 2002-06-15 Res Corp Technologies Inc Methoden zur feststellung von alzheimerscher krankheit
JP2978435B2 (ja) 1996-01-24 1999-11-15 チッソ株式会社 アクリロキシプロピルシランの製造方法
EP0948536B1 (fr) 1996-01-30 2007-06-13 The Scripps Research Institute Recepteur associe a la proteine g presentant un domaine extracellulaire agrandi
AU2063197A (en) 1996-03-04 1997-09-22 Massachusetts Institute Of Technology Materials and methods for enhancing cellular internalization
US5714352A (en) 1996-03-20 1998-02-03 Xenotech Incorporated Directed switch-mediated DNA recombination
US5882644A (en) 1996-03-22 1999-03-16 Protein Design Labs, Inc. Monoclonal antibodies specific for the platelet derived growth factor β receptor and methods of use thereof
US5874064A (en) 1996-05-24 1999-02-23 Massachusetts Institute Of Technology Aerodynamically light particles for pulmonary drug delivery
US5855913A (en) 1997-01-16 1999-01-05 Massachusetts Instite Of Technology Particles incorporating surfactants for pulmonary drug delivery
US5985309A (en) 1996-05-24 1999-11-16 Massachusetts Institute Of Technology Preparation of particles for inhalation
US6699658B1 (en) 1996-05-31 2004-03-02 Board Of Trustees Of The University Of Illinois Yeast cell surface display of proteins and uses thereof
WO1997046678A1 (fr) 1996-06-06 1997-12-11 Bayer Corporation Acides nucleiques et polypeptides apparentes a la preseniline
JPH109900A (ja) 1996-06-21 1998-01-16 Kanto Auto Works Ltd メ−タ指針
WO1999009150A1 (fr) 1996-08-15 1999-02-25 Bayer Corporation Methode permettant d'introduire des modifications dans un gene
CA2183901A1 (fr) 1996-08-22 1998-02-23 Johanna E. Bergmann Cibles pour le traitement et le diagnostic de la maladie d'alzheimer et du syndrome de down chez les humains
US7521531B2 (en) 1996-08-28 2009-04-21 Immunomedics, Inc. Methods for the purification of stable radioiodine conjugates
JPH1075781A (ja) 1996-08-30 1998-03-24 Sumitomo Electric Ind Ltd ヒトプロテアソームサブユニットp58蛋白質及びそれに特異的な抗体
EP0834561A1 (fr) 1996-09-27 1998-04-08 Rijksuniversiteit te Leiden Gène associé avec la migraine dans l'humain
US5916771A (en) 1996-10-11 1999-06-29 Abgenix, Inc. Production of a multimeric protein by cell fusion method
WO1998022120A1 (fr) 1996-11-19 1998-05-28 The Wistar Institute Of Anatomy & Biology Reactifs pour traiter et diagnostiquer la maladie d'alzheimer
US5919687A (en) 1996-12-24 1999-07-06 John Hopkins University Recombinant N-SMases and nucleic acids encoding same
PT954282E (pt) 1997-01-16 2005-06-30 Massachusetts Inst Technology Preparacao de particulas para inalacao
JPH10210982A (ja) 1997-01-31 1998-08-11 Fuji Yakuhin Kogyo Kk 新規なタンパク質
US20030068316A1 (en) * 1997-02-05 2003-04-10 Klein William L. Anti-ADDL antibodies and uses thereof
US6413940B1 (en) 1997-02-07 2002-07-02 Nymox Corporation Pharmaceutically active agents that impede the formation of amyloid by impeding the genesis of DMS
US7226730B1 (en) 1997-02-26 2007-06-05 The General Hospital Corporation Transgenic animals and cell lines for screening drugs effective for the treatment or prevention of Alzheimer's Disease
US7045531B1 (en) 1997-03-11 2006-05-16 The General Hospital Corporation Composition comprising a metal chelator and a method of treating amyloidosis by administering the metal chelator
JP4740426B2 (ja) 1997-03-17 2011-08-03 ビーティージー・インターナショナル・リミテッド 治療用組成物
US20020086847A1 (en) 1997-04-09 2002-07-04 Mindset Biopharmaceuticals (Usa) Recombinant antibodies specific for beta-amyloid ends, DNA encoding and methods of use thereof
US8173127B2 (en) 1997-04-09 2012-05-08 Intellect Neurosciences, Inc. Specific antibodies to amyloid beta peptide, pharmaceutical compositions and methods of use thereof
US6235883B1 (en) 1997-05-05 2001-05-22 Abgenix, Inc. Human monoclonal antibodies to epidermal growth factor receptor
EP1860187B1 (fr) 1997-05-15 2011-07-13 Genentech, Inc. Récepteur apo-2
KR100567277B1 (ko) 1997-07-21 2006-04-05 마토씨안-로저스, 알피 항-항-t 세포 수용체 브이베타 항체 또는 이 항체에 의해 인식되는 펩티드 및 내분비선 분비 조절 단백질 i(esrp1)을 사용하는 질병의 진단 및 치료 방법
IT1293511B1 (it) 1997-07-30 1999-03-01 Gentili Ist Spa Anticorpi monoclonali catalitici ad attivita' proteasica per la lisi selettiva della componente proteica di placche e aggregati correlati
ES2281135T3 (es) 1997-08-14 2007-09-16 Institut Pasteur Proteinas hibridas de un toxoide tetanico que migran de forma retrograda y transinaptica al snc.
US7923216B2 (en) 1997-08-14 2011-04-12 Institut Pasteur In vivo modulation of neuronal transport
EP1007092B1 (fr) 1997-08-26 2006-08-09 Amgen Fremont Inc. Procede d'inhibition d'activation de complement par la voie alterne
US6666935B1 (en) 1997-09-09 2003-12-23 The Regents Of The University Of California Sol-gel manufactured energetic materials
FR2768346B1 (fr) 1997-09-15 2002-04-19 Fond Jean Dausset Ceph Compose assurant l'inhibition de la preseniline 1 pour la preparation d'un medicament et agent de diagnostic
US20040185039A1 (en) 2002-08-30 2004-09-23 Heinz Kohler Therapeutic applications of noncovalent dimerizing antibodies
US5989463A (en) 1997-09-24 1999-11-23 Alkermes Controlled Therapeutics, Inc. Methods for fabricating polymer-based controlled release devices
SE512663C2 (sv) 1997-10-23 2000-04-17 Biogram Ab Inkapslingsförfarande för aktiv substans i en bionedbrytbar polymer
WO1999022024A1 (fr) 1997-10-24 1999-05-06 Cornell Research Foundation, Inc. Detection de maladies neurodegeneratives
US6710226B1 (en) 1997-12-02 2004-03-23 Neuralab Limited Transgenic mouse assay to determine the effect of Aβ antibodies and Aβ Fragments on alzheimer's disease characteristics
TWI239847B (en) 1997-12-02 2005-09-21 Elan Pharm Inc N-terminal fragment of Abeta peptide and an adjuvant for preventing and treating amyloidogenic disease
US6913745B1 (en) 1997-12-02 2005-07-05 Neuralab Limited Passive immunization of Alzheimer's disease
US6761888B1 (en) 2000-05-26 2004-07-13 Neuralab Limited Passive immunization treatment of Alzheimer's disease
US7964192B1 (en) 1997-12-02 2011-06-21 Janssen Alzheimer Immunotherapy Prevention and treatment of amyloidgenic disease
US6750324B1 (en) 1997-12-02 2004-06-15 Neuralab Limited Humanized and chimeric N-terminal amyloid beta-antibodies
US6787523B1 (en) 1997-12-02 2004-09-07 Neuralab Limited Prevention and treatment of amyloidogenic disease
US7179892B2 (en) 2000-12-06 2007-02-20 Neuralab Limited Humanized antibodies that recognize beta amyloid peptide
US6743427B1 (en) 1997-12-02 2004-06-01 Neuralab Limited Prevention and treatment of amyloidogenic disease
WO1999027949A1 (fr) 1997-12-03 1999-06-10 Brigham And Women's Hospital PROCEDES DE SUPPRESSION DES MODIFICATIONS LIEES AUX β-AMYLOIDES DANS LA MALADIE D'ALZHEIMER
EP1038958A4 (fr) 1997-12-15 2002-10-09 Kyowa Hakko Kogyo Kk PROTEINE Nap1 HUMAINE
US6730778B2 (en) 1997-12-19 2004-05-04 Pharmacia And Upjohn Company Human sel-10 polypeptides and polynucleotides that encode them
US6436989B1 (en) 1997-12-24 2002-08-20 Vertex Pharmaceuticals, Incorporated Prodrugs of aspartyl protease inhibitors
US7189703B2 (en) 1998-01-09 2007-03-13 Intracell, Llc Treatment and diagnosis of alzheimer's disease
MX2008014823A (es) 1998-02-11 2009-03-06 Neurochem Int Ltd Metodo para modular la activacion de macrofagos.
JP2002505097A (ja) 1998-03-03 2002-02-19 アブジェニックス インク. 治療薬としてのcd147結合分子
US6323218B1 (en) 1998-03-11 2001-11-27 The General Hospital Corporation Agents for use in the treatment of Alzheimer's disease
US20050112543A1 (en) 1998-03-11 2005-05-26 The General Hospital Corporation Method of screening for drugs useful in treating Alzheimer's disease
US20050059802A1 (en) 1998-04-07 2005-03-17 Neuralab Ltd Prevention and treatment of amyloidogenic disease
US20050059591A1 (en) 1998-04-07 2005-03-17 Neuralab Limited Prevention and treatment of amyloidogenic disease
NO314086B1 (no) 1998-05-08 2003-01-27 Gemvax As Peptider og farmasöytiske sammensetninger inneholdende disse, nukleinsyresekvenser som koder for slike peptider, plasmider og virusvektoreromfattende slike DNA-sekvenser samt anvendelse av disse for fremstilling avfarmasöytiske preparater til
WO1999058157A1 (fr) 1998-05-08 1999-11-18 Cramer Donald V Procede d'inhibition de rejet induit par anticorps de tissus heterologues
AU3726299A (en) 1998-05-15 1999-12-06 Neurochem, Inc. Use of amyloid inhibitors for modulating neuronal cell death
US20030147882A1 (en) 1998-05-21 2003-08-07 Alan Solomon Methods for amyloid removal using anti-amyloid antibodies
DE69913520T2 (de) 1998-06-01 2004-11-25 Ortho-Mcneil Pharmaceutical, Inc. Tetrahydronaphtalene verbindungen und deren verwendung zur behandlung von neurodegenerativen krankheiten
JP2000050885A (ja) 1998-06-02 2000-02-22 Fuji Chemical Industries Ltd カテプシンに対する抗体およびそれらの利用
DE69907456T2 (de) 1998-06-24 2004-03-25 Advanced Inhalation Research, Inc., Cambridge Grosse poröse partikel ausgestossen von einem inhalator
DK1092767T3 (da) 1998-07-02 2006-11-27 Fuso Pharmaceutical Ind Serinproteasespecifikke monoklonale antistoffer og anvendelse deraf
EP1105427A2 (fr) 1998-08-17 2001-06-13 Abgenix, Inc. Production de molecules modifiees avec demi-vie serique prolongee
US20030109672A1 (en) 1998-09-01 2003-06-12 Genentech, Inc. Secreted and transmembrane polypeptides and nucleic acids encoding the same
JP4403443B2 (ja) 1998-09-17 2010-01-27 大塚製薬株式会社 Ly6h遺伝子
US7083950B2 (en) 1998-09-25 2006-08-01 Regeneron Pharmaceuticals, Inc. High affinity fusion proteins and therapeutic and diagnostic methods for use
AU5999199A (en) 1998-09-29 2000-04-17 Kyowa Hakko Kogyo Co. Ltd. Novel antibodies, drugs containing these antibodies and methods for screening compounds by using these antibodies
US6660843B1 (en) 1998-10-23 2003-12-09 Amgen Inc. Modified peptides as therapeutic agents
WO2000032805A1 (fr) 1998-12-02 2000-06-08 The Trustees Of The University Of Pennsylvania Procedes et compositions permettant de determiner la peroxydation des lipides dans des syndromes et maladies lies au stress du aux oxydants
EP1731913A3 (fr) 1998-12-02 2007-01-17 The Trustees Of The University Of Pennsylvania Procédés et compositions permettant de déterminer la peroxydation des lipides dans des syndromes et maladies liés au stress du aux oxydants
ATE364617T1 (de) 1998-12-14 2007-07-15 Univ Miami Fragmente des wachstumsfaktors für bindegewebe (ctgf) und verfahren und anwendungen davon
RS51309B (sr) 1998-12-23 2010-12-31 Pfizer Inc. Humana monoklonalna antitela za ctla-4
DE19902550A1 (de) 1999-01-22 2000-07-27 Memorec Medical Molecular Rese Aspartatprotease
US20030185826A1 (en) 1999-02-24 2003-10-02 Tobinick Edward L. Cytokine antagonists for the treatment of localized disorders
FR2791263B1 (fr) 1999-03-26 2001-04-27 Halina Zofia Malina Preparations des medicaments bases sur une reponse immunitaire contre l'accumulation de proteines modifiees par l'acide xanthurenique
ES2571230T3 (es) 1999-04-09 2016-05-24 Kyowa Hakko Kirin Co Ltd Procedimiento para controlar la actividad de una molécula inmunofuncional
US7527787B2 (en) 2005-10-19 2009-05-05 Ibc Pharmaceuticals, Inc. Multivalent immunoglobulin-based bioactive assemblies
US6787637B1 (en) 1999-05-28 2004-09-07 Neuralab Limited N-Terminal amyloid-β antibodies
PE20010212A1 (es) 1999-06-01 2001-02-22 Neuralab Ltd Composiciones del peptido a-beta y procesos para producir las mismas
UA81216C2 (en) 1999-06-01 2007-12-25 Prevention and treatment of amyloid disease
US20030199103A1 (en) 1999-06-03 2003-10-23 Curagen Corporation Novel amino acid sequences for human epidermal growth factor-like polypeptides
JP2000354487A (ja) 1999-06-15 2000-12-26 Takashi Muramatsu ミッドカイン受容体
ATE405636T1 (de) 1999-06-16 2008-09-15 Boston Biomedical Res Inst Immunologische kontrolle des beta-amyloid gehaltes in vivo
US20020002270A1 (en) 1999-06-16 2002-01-03 Raymond P. Zinkowski Purified antigen for alzheimer's disease, and methods of obtaining and using same
US7605238B2 (en) 1999-08-24 2009-10-20 Medarex, Inc. Human CTLA-4 antibodies and their uses
CA2381770C (fr) 1999-08-24 2007-08-07 Medarex, Inc. Anticorps contre l'antigene ctla-4 humain et utilisation
EP1210464B1 (fr) 1999-09-01 2004-11-24 EVOTEC Neurosciences GmbH Procede de diagnostic ou de pronostic de la degenerescence maculaire liee a l'age
US20040013647A1 (en) 1999-09-03 2004-01-22 Ramot At Tel-Aviv University Ltd. Methods and compositions for treating a plaque-forming disease
IL142948A0 (en) 1999-09-03 2002-04-21 Univ Ramot Agents and compositions and methods utilizing same useful in diagnosing and/or treating or preventing plaque forming diseases
US6294171B2 (en) 1999-09-14 2001-09-25 Milkhaus Laboratory, Inc. Methods for treating disease states comprising administration of low levels of antibodies
JP2001122900A (ja) 1999-10-21 2001-05-08 Yasukazu Tanuma 抗−DNaseγ抗体並びにその製造及び使用
WO2001032712A2 (fr) 1999-11-03 2001-05-10 Maxygen, Inc. Generation de diversite d'anticorps
US20020094335A1 (en) 1999-11-29 2002-07-18 Robert Chalifour Vaccine for the prevention and treatment of alzheimer's and amyloid related diseases
CN1433321A (zh) 1999-11-29 2003-07-30 尼奥切姆公司 预防和治疗Alzheimer症和其他与淀粉样蛋白有关的疾病的疫苗
US20070135337A2 (en) 1999-11-29 2007-06-14 Neurochem (International) Limited Vaccine for the Prevention and Treatment of Alzheimer's and Amyloid Related Diseases
CA2393763A1 (fr) 1999-12-08 2001-06-14 Mindset Biopharmaceuticals (Usa), Inc. Peptides chimeriques comme immunogenes, anticorps contre ces immunogenes et techniques d'immunisation utilisant ces peptides chimeriques ou ces anticorps
EP1752472A3 (fr) 1999-12-08 2007-04-25 Intellect Neurosciences, Inc. Peptides amyloides beta chimériques
JP2001231578A (ja) 1999-12-09 2001-08-28 Kyowa Hakko Kogyo Co Ltd Il−1ファミリーに属する蛋白質
EP1251837A2 (fr) 1999-12-23 2002-10-30 Neurochem, Inc. Composes et methodes permettant la modulation de l'angiopathie cerebrale amyloide
US20030077757A1 (en) 2000-01-11 2003-04-24 Andrews William H. Method of treating aging-related disorders
US6785434B2 (en) 2000-01-17 2004-08-31 Avanex Corporation Attenuator integrated with modulator and transmitting module for WDM systems using the same
WO2001053457A2 (fr) * 2000-01-21 2001-07-26 University Of Connecticut Health Center Vaccins contre certains troubles neurodegeneratifs
US6806254B2 (en) 2000-02-03 2004-10-19 Nuvelo, Inc. Methods and materials relating to alpha-2-macroglobulin-like polypeptides and polynucleotides
US20020182660A1 (en) 2000-02-18 2002-12-05 Fong Kei-Lai L. N- and C-terminus specific immunoassays for full length beta-amyloid peptide-Abeta(1-40), Abeta(1-39), Abeta(1-40), Abeta(1-42) , and Abeta(1-43)
MXPA02007796A (es) 2000-02-21 2003-12-08 Pharmexa As Metodo novedoso para la disminucion de cuerpos amiloides.
EP1259251B1 (fr) 2000-02-21 2005-10-19 Pharmexa A/S Nouvelle methode de regulation negative d'amyloide
AU4178601A (en) 2000-02-24 2001-09-03 Univ Washington Humanized antibodies that sequester abeta peptide
EP1130032A1 (fr) 2000-02-28 2001-09-05 Gesellschaft für biotechnologische Forschung mbH (GBF) Anticorps monochaines reconnaissant le récepteur humain de type 2 du facteur de croissance vasculaire endothéliale (VEGFR-2/KDR)
GB0006398D0 (en) 2000-03-16 2000-05-03 Novartis Ag Organic compounds
WO2001071351A1 (fr) 2000-03-22 2001-09-27 The General Hospital Corporation Procede destine au traitement des maladies neurodegeneratives
WO2001075165A2 (fr) 2000-03-30 2001-10-11 Elan Pharmaceuticals, Inc. Marqueurs et methodes de criblage pour maladies neurodegeneratives
AU2001249835A1 (en) 2000-04-03 2001-10-15 Oxford Glycosciences (Uk) Ltd. Diagnosis and treatment of alzheimer's disease
US7371365B2 (en) 2000-04-04 2008-05-13 Mayo Foundation For Medical Education And Research Methods for detecting parenchymal plaques in vivo
AUPQ712000A0 (en) 2000-04-27 2000-05-18 Medvet Science Pty. Ltd. Antigenic peptide fragments of VapA protein, and uses thereof
US20080009467A1 (en) 2000-05-01 2008-01-10 Accera, Inc. Combinations of medium chain triglycerides and therapeutic agents for the treatment and prevention of alzheimers disease and other diseases resulting from reduced neuronal metabolism
WO2001083525A2 (fr) 2000-05-03 2001-11-08 Amgen Inc. Peptides modifies utilises comme agents therapeutiques
AU7487301A (en) 2000-05-22 2001-12-03 Univ New York Synthetic immunogenic but non-amyloidogenic peptides homologous to amyloid beta for induction of an immune response to amyloid beta and amyloid deposits
JP2004500873A (ja) 2000-06-22 2004-01-15 ジェネンテック・インコーポレーテッド アゴニスト抗−trk−cモノクローナル抗体
JP4252195B2 (ja) 2000-06-27 2009-04-08 新日本無線株式会社 高周波線路の変換器
US7449308B2 (en) 2000-06-28 2008-11-11 Glycofi, Inc. Combinatorial DNA library for producing modified N-glycans in lower eukaryotes
DK1296705T3 (da) * 2000-06-28 2012-09-17 Prana Biotechnology Ltd Beta-amyloid-oligomerer til anvendelse til behandling, lindring eller forebyggelse af Alzheimers sygdom
EP2322644A1 (fr) 2000-06-28 2011-05-18 GlycoFi, Inc. Procédé de production de glycoprotéines modifiées
US6686449B2 (en) 2000-06-30 2004-02-03 Pharmacia & Upjohn Company Mutant presenilin 1 polypeptides
EP1297132A1 (fr) 2000-07-06 2003-04-02 Vlaams Interuniversitair Instituut voor Biotechnologie vzw. Nouvelle mutation app associee a une pathologie inhabituelle de la maladie d'alzheimer
AU2007200047B2 (en) 2000-07-07 2009-11-26 Bioarctic Neuroscience Ab Prevention and treatment of Alzheimer's disease
WO2002003911A2 (fr) 2000-07-07 2002-01-17 Lars Lannfelt Prevention et traitement de la maladie d'alzheimer
US6524819B1 (en) 2000-07-11 2003-02-25 Incyte Genomics, Inc. Down syndrome critical region 1-like proteins
EP1172378A1 (fr) 2000-07-12 2002-01-16 Richard Dr. Dodel Anticorps humains anti-beta-amyloid et leur utilisation pour le traitement de la maladie d'Alzheimer
US20020009445A1 (en) 2000-07-12 2002-01-24 Yansheng Du Human beta-amyloid antibody and use thereof for treatment of alzheimer's disease
JP2002040023A (ja) 2000-07-28 2002-02-06 Mitsubishi Chemicals Corp アルツハイマー病の検出方法
US20070009931A1 (en) 2000-08-04 2007-01-11 Kirsch Wolff M Negative correlation between IRP-2 and Transferrin receptor expression as a diagnostic of Alzheimer's disease
PT1317479E (pt) 2000-09-06 2009-10-29 Univ Pasteur Métodos e composições para doenças associadas à amiloidose
GB0024446D0 (en) 2000-10-05 2000-11-22 Glaxo Group Ltd Protein
IT1319277B1 (it) 2000-10-24 2003-09-26 Chiesi Farma Spa Proteine di fusione utili per il trattamento di immunizzazione dellamalattia di alzheimer.
US6962793B2 (en) 2000-10-27 2005-11-08 Mount Sinai Hospital Methods for detecting Alzheimers disease
WO2002036614A2 (fr) 2000-11-01 2002-05-10 Insight Biotechnology Limited Peptides destines a une utilisation dans le traitement de la maladie d'alzheimer
WO2002094870A2 (fr) 2000-11-02 2002-11-28 Curagen Corporation Proteines et acides nucleiques codant pour ces proteines
DE10055703A1 (de) 2000-11-02 2002-05-08 Peter F Pascoe Verhinderung der Zellzerstörung und Beseitigung sklrotischer Amyloide verursacht durch organspezifische Antikörperaggregate
EP1341548A4 (fr) 2000-11-03 2006-06-14 Massachusetts Inst Technology Methodes d'identification de traitements de la neurotoxicite dans la maladie d'alzheimer engendree par des peptides $g(b)-amyloides
US20060062786A1 (en) 2000-11-08 2006-03-23 Human Genome Sciences, Inc. Antibodies that immunospecifically bind to TRAIL receptors
DE60126980T2 (de) 2000-11-27 2007-11-08 Praecis Pharmaceuticals Inc., Waltham Therapeutische agentien und methoden ihrer verwendung zur behandlung von amyloidogenen erkrankungen
TWI255272B (en) 2000-12-06 2006-05-21 Guriq Basi Humanized antibodies that recognize beta amyloid peptide
GB0100110D0 (en) 2001-01-04 2001-02-14 Univ Leeds Modulation of calcium channel activity
DE10101430B4 (de) 2001-01-13 2008-10-02 Fraunhofer-Gesellschaft zur Förderung der angewandten Forschung e.V. Lösliche cyclische Analoga zur Modulation der Amyloidogenese
US20020132758A1 (en) 2001-01-18 2002-09-19 Shell John W. Method for identifying compounds to treat medical pathologies associated with molecular crystallization
US7264810B2 (en) 2001-01-19 2007-09-04 Cytos Biotechnology Ag Molecular antigen array
AT500379B8 (de) 2001-02-02 2009-08-15 Axon Neuroscience Tau-proteine
US7175988B2 (en) 2001-02-09 2007-02-13 Human Genome Sciences, Inc. Human G-protein Chemokine Receptor (CCR5) HDGNR10
US20040191264A1 (en) 2001-02-19 2004-09-30 Nielsen Klaus Gregorius Synthetic vaccine agents
JP4659236B2 (ja) 2001-03-01 2011-03-30 大塚製薬株式会社 細胞傷害活性の測定法
US6815175B2 (en) 2001-03-16 2004-11-09 Cornell Research Foundation, Inc. Anti-amyloid peptide antibody based diagnosis and treatment of a neurological disease or disorder
FR2822238B1 (fr) 2001-03-16 2003-08-29 Gemac Methode et trousse pour le suivi des maladies neurodegeneratives
DE10117281A1 (de) 2001-04-06 2002-10-24 Inst Molekulare Biotechnologie Peptid zur Diagnose und Therapie der Alzheimer-Demenz
CA2443770A1 (fr) 2001-04-23 2002-10-31 Curagen Corporation Proteines et acides nucleiques codant pour celles-ci
US6451547B1 (en) 2001-04-25 2002-09-17 Syn X Pharma Process for differential diagnosis of Alzheimer's dementia and device therefor
EP1385545B1 (fr) 2001-04-30 2009-01-07 Eli Lilly And Company Anticorps humanises reconnaissant le peptide amyloide beta
US7320790B2 (en) 2001-04-30 2008-01-22 Eli Lilly And Company Humanized antibodies
US7196163B2 (en) 2001-05-22 2007-03-27 Merk & Co., Inc. Assays using amyloid precursor proteins with modified β-secretase cleavage sites to monitor β-secretase activity
EP1395275B1 (fr) 2001-05-22 2008-11-12 Merck & Co., Inc. Substrat de beta-secretase et ses utilisations
US6906169B2 (en) 2001-05-25 2005-06-14 United Biomedical, Inc. Immunogenic peptide composition comprising measles virus Fprotein Thelper cell epitope (MUFThl-16) and N-terminus of β-amyloid peptide
ES2228697T3 (es) 2001-06-12 2005-04-16 Wiltfang, Jens Anticuerpo monoclonal, mab 1e8, que es especifico para los dos primeros aminoacidos de peptidos beta-amiloides y su utilizacion en la deteccion de peptidos beta-amiloides y/o sapp alfa.
US7595378B2 (en) 2001-06-13 2009-09-29 Genmab A/S Human monoclonal antibodies to epidermal growth factor receptor (EGFR)
KR20090125840A (ko) 2001-06-13 2009-12-07 젠맵 에이/에스 표피 성장 인자 수용체 (egfr)에 대한 인간 모노클로날 항체
US7094884B2 (en) 2001-06-22 2006-08-22 Roche Diagnostics Corporation Soluble complexes of amylod β peptide and peptidyl prolyl isomerase chaperone and methods of making and using them
US20020197258A1 (en) 2001-06-22 2002-12-26 Ghanbari Hossein A. Compositions and methods for preventing protein aggregation in neurodegenerative diseases
CN1396183A (zh) 2001-07-13 2003-02-12 张小如 降低脑内与老年痴呆有关的淀粉样变纤维的融合人抗体
WO2003008626A2 (fr) 2001-07-20 2003-01-30 Oregon Health And Science University Nouveaux acides nucleiques humains codant pour une pantothenate kinase et procedes d'utilisation
DE60226036T9 (de) 2001-08-03 2016-09-29 Medical & Biological Laboratories Co., Ltd. ANTIKÖRPER, DER DAS GM1-GANGLIOSID-GEBUNDENE AMYLOID-b-PROTEIN ERKENNT, UND DNA, DIE FÜR DIESEN ANTIKÖRPER CODIERT
JP4320694B2 (ja) 2001-08-08 2009-08-26 株式会社オーク製作所 多重露光描画装置および多重露光式描画方法
WO2003014329A2 (fr) 2001-08-10 2003-02-20 University Of South Florida Modulation de l'angiogenese par des peptides a-beta
DK1944040T3 (da) 2001-08-17 2012-10-29 Univ Washington Analysefremgangsmåde for Alzheimers sygdom
CA2457145C (fr) 2001-08-17 2010-12-21 Washington University Procede de dosage destine a la maladie d'alzheimer
EP1519740A4 (fr) 2001-08-17 2005-11-09 Lilly Co Eli Amelioration rapide des processus cognitifs dans les etats pathologiques lies a l'a-beta
MY144532A (en) 2001-08-20 2011-09-30 Lundbeck & Co As H Novel method for down-regulation of amyloid
US20030082191A1 (en) 2001-08-29 2003-05-01 Poduslo Joseph F. Treatment for central nervous system disorders
EP1438400B1 (fr) 2001-10-01 2009-06-17 Dyax Corp. Vecteurs d'affichage eukaryotes multichaine et leurs utilisations
WO2003028543A2 (fr) 2001-10-03 2003-04-10 Pfizer Products Inc. Molecules d'acide nucleique, polypeptides et utilisations associees comprenant le diagnostic et le traitement de la maladie d'alzheimer
DE60225821T2 (de) 2001-10-04 2009-04-30 Immuno-Biological Laboratories Co., Ltd., Takasaki Reagens zum Nachweis eines Risikofaktors der Alzheimer-Krankheit, Nachweiskit dafür und Verfahren zum Nachweis eines Risikofaktors der Alzheimer-Krankheit unter ihrer Verwendung
US20030099635A1 (en) 2001-10-04 2003-05-29 Protein Therapeutics, Inc. Use of oral gammaglobulin for the treatment of immune-mediated diseases
GB0124317D0 (en) 2001-10-10 2001-11-28 Celltech R&D Ltd Biological products
HUP0600342A3 (en) 2001-10-25 2011-03-28 Genentech Inc Glycoprotein compositions
EP1448601A4 (fr) 2001-11-02 2006-04-26 Diagenics Internat Corp Methodes et compositions d'anticorps monoclonaux specifiques des proteines beta-amyloides
WO2003045128A2 (fr) 2001-11-21 2003-06-05 New York University Polypeptides immunogenes synthetiques ne formant pas de depots et peptides homologues destines a des repetitions amyloide $g(b), proteine prion, amyline, $g(a)-synucleine, ou polyglutamine pour induction d'une reponse immunitaire a ceux-ci
US7179606B2 (en) 2001-11-23 2007-02-20 Syn X Pharma, Inc. IG heavy chain, IG kappa, IG lambda biopolymer markers predictive of Alzheimer's disease
US7026129B2 (en) 2001-11-23 2006-04-11 Syn X Pharma, Inc. IG lambda biopolymer markers predictive of Alzheimers disease
DE10158180A1 (de) 2001-11-28 2003-09-11 Biovision Ag Verfahren zum Nachweis von Morbus Alzheimer und zur Unterscheidung von Morbus Alzheimer gegenüber anderen demenziellen Erkrankungen, zugehörige Peptide und deren Verwendung
AU2002363861A1 (en) 2001-11-30 2003-06-10 Crucell Holland B.V. Antigen presenting cell targeting conjugate, an intigen presenting cell contacted with such conjugate, their use for vaccination or as medicament, and methods for their production or generation
JP2005521645A (ja) 2001-12-04 2005-07-21 ベン グリオン ユニバーシティ オブ ザ ネジェブ リサーチ アンド ディベラップメント オーソリティ 器官特異的薬物ターゲティング用両親媒性化合物及び小胞/リポソーム
WO2003051374A2 (fr) 2001-12-17 2003-06-26 New York State Office Of Mental Health SEQUESTRATION DE Aβ DANS LA REGION PERIPHERIQUE EN L'ABSENCE D'AGENTS IMMUNOMODULATEURS COMME APPROCHE THERAPEUTIQUE POUR LE TRAITEMENT OU LA PREVENTION DES MALADIES LIEES A LA BETA-AMYLOIDE
CA2500462A1 (fr) 2001-12-26 2004-03-25 Universidad De Zaragoza Anticorps polyclonaux, methode de preparation et utilisation
US7781396B2 (en) 2002-01-31 2010-08-24 Tel Aviv University Future Technology Development L.P. Peptides directed for diagnosis and treatment of amyloid-associated disease
US20070021345A1 (en) 2003-06-30 2007-01-25 Ehud Gazit Peptides antibodies directed thereagainst and methods using same for diagnosing and treating amyloid-associated diseases
US20050153381A1 (en) 2002-02-14 2005-07-14 Marusich Michael F. Immunocapture of mitochondrial protein complexes
AR038568A1 (es) 2002-02-20 2005-01-19 Hoffmann La Roche Anticuerpos anti-a beta y su uso
WO2003074004A2 (fr) 2002-03-01 2003-09-12 Szu-Yi Chou Procede de production d'antigenes
KR20040088572A (ko) 2002-03-01 2004-10-16 이뮤노메딕스, 인코오포레이티드 제거율 증강을 위한 양특이성 항체 점 돌연변이들
EP2292247A3 (fr) 2002-03-05 2011-10-05 Ramot at Tel Aviv University Ltd. Composition immunisante et procédé permettant d'induire une réponse immunitaire contre le site de clivage de la bêta-sécrétase
MY139983A (en) 2002-03-12 2009-11-30 Janssen Alzheimer Immunotherap Humanized antibodies that recognize beta amyloid peptide
US8420353B2 (en) 2002-03-22 2013-04-16 Aprogen, Inc. Humanized antibody and process for preparing same
US20030190689A1 (en) 2002-04-05 2003-10-09 Cell Signaling Technology,Inc. Molecular profiling of disease and therapeutic response using phospho-specific antibodies
US7122374B1 (en) 2002-04-09 2006-10-17 Takaomi Saido Amyloid beta-protein 3(pE)-42 antibodies and uses thereof
WO2003086310A2 (fr) 2002-04-12 2003-10-23 Ramot At Tel Aviv University Ltd. Prevention de l'inflammation du cerveau en tant que resultat d'une reponse auto-immune induite
PL209696B1 (pl) 2002-04-19 2011-10-31 Univ Toronto Peptyd, kompozycja peptydowa, kompozycja immunogenna, zastosowania kompozycji immunogennej oraz sposób określania czy związek stanowi inhbitor odkładania się i tworzenia włókienek amyloidu
WO2003091734A1 (fr) 2002-04-24 2003-11-06 Evotec Neurosciences Gmbh Utilisation a des fins diagnostiques et therapeutiques du gene et de la proteine ensadine-0477 pour le traitement de maladies neurodegeneratives
JP2005523335A (ja) 2002-04-25 2005-08-04 イーライ・リリー・アンド・カンパニー 高齢被検体の不安障害および気分障害の治療方法
US20060257420A1 (en) 2002-04-26 2006-11-16 Cel-Sci Corporation Methods of preparation and composition of peptide constructs useful for treatment of autoimmune and transplant related host versus graft conditions
DE10221052A1 (de) 2002-05-10 2003-12-04 Transmit Technologietransfer Wirkstoffe zu Therapie, Diagnostik und Prophylaxe von Erkrankungen, bei denen abnorme Proteinstrukturen auftreten
WO2003100419A1 (fr) 2002-05-27 2003-12-04 Bioceros B.V. Procedes d'utilisation de la voie de cd163 pour moduler une reponse immunitaire
AU2003241131A1 (en) 2002-06-14 2003-12-31 Brainsgate Ltd. Methods and systems for management of alzheimer's disease
AU2003278497A1 (en) 2002-06-20 2004-01-06 Evotec Neurosciences Gmbh Diagnostic and therapeutic use of ras-gtpase-activating sh3-domain-binding protein 2 (g3bp2) for neurodegenerative diseases
WO2004003563A2 (fr) 2002-06-27 2004-01-08 Evotec Neurosciences Gmbh Utilisation diagnostique et therapeutique de la proteine et du gene ensadin-0581 dans le cadre des maladies neurodegeneratives
ATE328906T1 (de) 2002-06-28 2006-06-15 Domantis Ltd Dual-specifische liganden mit erhöhter halbwertszeit
DK1521831T3 (da) 2002-07-12 2008-06-30 Axon Neuroscience Transgent dyr der udtrykker trunkeret alzheimers tauprotein
AU2003256578A1 (en) 2002-07-17 2004-02-02 Intellect Neurosciences, Inc. Peptides and methods of screening immunogenic peptide vaccines against alzheimer's disease
EP1544210A4 (fr) 2002-07-18 2006-01-25 Masayasu Okochi Nouveaux polypeptides d'origine notch, biomarqueurs et reactifs faisant appel a ces derniers
NZ598346A (en) 2002-07-19 2013-10-25 Abbvie Biotechnology Ltd Treatment of tnf alpha related disorders
KR101070078B1 (ko) 2002-07-19 2011-10-04 노파르티스 파르마 아게 아밀로이드 베타1-6 항원 어레이를 포함하는 백신 조성물
EP1523499A2 (fr) 2002-07-24 2005-04-20 Innogenetics N.V. Fragments du peptide beta-amyloide en tant que cibles pour la vaccination contre la maladie d'alzheimer
US7250551B2 (en) 2002-07-24 2007-07-31 President And Fellows Of Harvard College Transgenic mice expressing inducible human p25
SE0202880D0 (sv) 2002-07-26 2002-09-30 Wieslab Ab Complement system deficiency assay
EP1543331B1 (fr) 2002-07-30 2009-02-11 The J. David Gladstone Institutes Procede de diagnostic de la maladie d'alzheimer
US20040138296A1 (en) 2002-08-12 2004-07-15 Pharmacia Corporation Amyloid immunization and Cox-2 inhibitors for the treatment of alzheimer's disease
US7252953B2 (en) 2002-08-13 2007-08-07 United States Of America Department Of Veterans Affairs Method of detecting and preventing Alzheimer's disease, particularly at prodromal and early stages
WO2004016655A1 (fr) 2002-08-14 2004-02-26 Mitsubishi Chemical Corporation Anticorps specifique a une proteine-$g(t) centrale
AU2003259965A1 (en) 2002-08-20 2004-03-11 Neurogenetics, Inc. Methods and compositions for modulating amyloid beta
AU2003266302A1 (en) 2002-08-23 2004-03-11 Proteosys Ag Method for the diagnosis of alzheimer disease
AU2003270643A1 (en) 2002-09-12 2004-04-30 The Regents Of The University Of California Immunogens and corresponding antibodies specific for high molecular weight aggregation intermediates common to amyloids formed from proteins of differing sequence
US7238488B2 (en) 2002-09-13 2007-07-03 Grace Maresh Therapeutic and diagnostic applications of perlecan domain I splice variants
US20070010657A1 (en) 2002-09-13 2007-01-11 Rainer Klocke Cytoplasmic dynein heavy chain 1 genes, expression products, non-human animal model uses in human neurological diseases
US20040127471A1 (en) 2002-09-17 2004-07-01 Barry Reisberg Methods of treating age associated memory impairment (AAMI), mild cognitive impairment (MCI), and dementias with cell cycle inhibitors
JP4242128B2 (ja) 2002-09-18 2009-03-18 武田薬品工業株式会社 脳アミロイドーシス予防・治療薬のスクリーニング方法
WO2004029629A1 (fr) 2002-09-27 2004-04-08 Janssen Pharmaceutica N.V. Anticorps monoclonaux beta-amyloide n-11 tronques, compositions, methodes et utilisations
US7541440B2 (en) 2002-09-30 2009-06-02 Immunomedics, Inc. Chimeric, human and humanized anti-granulocyte antibodies and methods of use
JP2006508072A (ja) * 2002-10-01 2006-03-09 ノースウエスタン ユニバーシティ アミロイドベータ由来拡散性リガンド(ADDLs)、ADDL代替物、ADDL結合性分子、およびそれらの使用
US20070213512A1 (en) 2002-10-01 2007-09-13 Krafft Grant A Amyloid beta peptide analogs and assemblies thereof
AU2003272925A1 (en) 2002-10-04 2004-04-23 Techno Network Shikoku Co., Ltd. Monoclonal antibody against subtilisin-like proprotein convertase pace4 and utilization thereof
JP2006514824A (ja) 2002-10-09 2006-05-18 アクティブクス バイオサイエンスィズ インコーポレイテッド 活性に基づくプローブ,およびその製造および使用方法
PL377769A1 (pl) 2002-10-09 2006-02-20 Rinat Neuroscience Corp. Sposób leczenia choroby Alzheimera z zastosowaniem przeciwciał skierowanych przeciw peptydowi beta amyloidu i ich kompozycje
AU2003279312A1 (en) 2002-10-24 2004-05-13 Evotec Neurosciences Gmbh Diagnostic and therapeutic use of ensadin-0289 gene and protein for neurodegenerative diseases
US20080014194A1 (en) 2003-10-31 2008-01-17 Elan Pharmaceuticals, Inc. Prevention and Treatment of Synucleinopathic and Amyloidogenic Disease
TW200509968A (en) 2002-11-01 2005-03-16 Elan Pharm Inc Prevention and treatment of synucleinopathic disease
FR2846667B1 (fr) 2002-11-06 2004-12-31 Pasteur Institut Fragments variables d'anticorps de camelides a chaine unique diriges contre le peptide beta-amyloide 1-42 et leurs applications pour le diagnostic et le traitement des maladies neuroagregatives
WO2004043989A2 (fr) 2002-11-07 2004-05-27 Medarex, Inc. Anticorps monoclonaux humains diriges contre l'heparanase
WO2004045525A2 (fr) 2002-11-15 2004-06-03 Morehouse School Of Medicine Anticorps anti-chimiokines et anticorps anti-recepteurs associes et utilisations de ces anticorps pour inhiber des inflammations
CN100450551C (zh) 2002-11-29 2009-01-14 中国医学科学院基础医学研究所 用于治疗和预防阿尔茨海默病的重组腺相关病毒基因疫苗及其用途
DE10256900A1 (de) 2002-11-29 2004-06-24 Nemod Immuntherapie Ag Tumorspezifische Erkennungsmoleküle
CN1878795A (zh) 2002-12-02 2006-12-13 阿布格尼克斯公司 针对磷脂酶a2的抗体及其应用
WO2004056318A2 (fr) 2002-12-19 2004-07-08 New York University Methode permettant de traiter une maladie amyloide
WO2004058239A1 (fr) 2002-12-24 2004-07-15 Neurochem (International) Limited Formulations therapeutiques destinees au traitement de maladies liees au peptide beta-amyloide
US20050031651A1 (en) 2002-12-24 2005-02-10 Francine Gervais Therapeutic formulations for the treatment of beta-amyloid related diseases
GB0230203D0 (en) 2002-12-27 2003-02-05 Domantis Ltd Fc fusion
AT413945B (de) 2003-01-14 2006-07-15 Mattner Frank Dr Impfstoff für die alzheimer-krankheit
CA2514153A1 (fr) 2003-01-22 2004-08-05 Takeda Pharmaceutical Company Limited Anticorps et utilisation de ce dernier
WO2004065569A2 (fr) 2003-01-23 2004-08-05 The Regents Of The University Of California Anticorps multifonctionnels
US7563869B2 (en) 2003-01-23 2009-07-21 Ono Pharmaceutical Co., Ltd. Substance specific to human PD-1
DE10303974A1 (de) * 2003-01-31 2004-08-05 Abbott Gmbh & Co. Kg Amyloid-β(1-42)-Oligomere, Verfahren zu deren Herstellung und deren Verwendung
PL378571A1 (pl) 2003-02-01 2006-05-02 Neuralab Limited Czynna immunizacja dla wytworzenia przeciwciał przeciw rozpuszczalnemu A-ß
US7223393B2 (en) 2003-02-07 2007-05-29 Pdl Biopharma, Inc Amphiregulin antibodies and their use to treat cancer and psoriasis
EP1596809B1 (fr) 2003-02-10 2010-05-26 Applied Molecular Evolution, Inc. Molecules de liaison au peptide abeta
US20040242845A1 (en) 2003-02-21 2004-12-02 Nicolau Yves Claude Methods and compositions comprising supramolecular antigenic constructs and antibodies elicited against them
US8663650B2 (en) 2003-02-21 2014-03-04 Ac Immune Sa Methods and compositions comprising supramolecular constructs
US20060188951A1 (en) 2003-02-24 2006-08-24 In Hee Mook Method for measuring the level of anti-beta-amyloid antibody in body fluids and diagnostic kit for alzheimer's disease using same
US20040223970A1 (en) 2003-02-28 2004-11-11 Daniel Afar Antibodies against SLC15A2 and uses thereof
US20060104968A1 (en) 2003-03-05 2006-05-18 Halozyme, Inc. Soluble glycosaminoglycanases and methods of preparing and using soluble glycosaminogly ycanases
DK2163643T3 (en) 2003-03-05 2015-03-23 Halozyme Inc Soluble hyaluronidaseglycoprotein (sHASEGP), process for preparing the same, pharmaceutical compositions and uses thereof covered
WO2004085712A2 (fr) 2003-03-24 2004-10-07 Penn State Research Foundation Materiaux polymeres multifonctionnels et leurs utilisations
JP4939929B2 (ja) 2003-03-26 2012-05-30 ポール,サッドヒル タンパク質分解抗体および共有結合抗体
CN1189210C (zh) 2003-03-28 2005-02-16 万选才 Cb与生物活性多肽的偶联物及其医药用途
AU2004274390A1 (en) 2003-03-28 2005-03-31 Jacqueline M. Benson Anti-amyloid antibodies, compositions, methods and uses
US7632816B2 (en) 2003-03-28 2009-12-15 New York University Treatment of Alzheimer amyloid deposition
CA2522067C (fr) 2003-04-09 2010-07-06 Canadian Blood Services Detection, caracterisation et traitement d'infections virales, et procedes associes
EP1469312A1 (fr) 2003-04-18 2004-10-20 Friedrich-Alexander-Universität Erlangen-Nürnberg Le diagnostic de la maladie d'Alzheimer
US20060240485A1 (en) 2003-04-24 2006-10-26 Universitat Zurich Method of monitoring immunotherapy
CA2524737A1 (fr) 2003-05-06 2005-02-24 Human Genome Sciences, Inc. Anticorps se liant de maniere immunospecifique aux recepteurs trail
US20040223912A1 (en) 2003-05-07 2004-11-11 Montalto Michael Christopher Compositions and methods for non-invasive imaging of soluble beta-amyloid
ES2246178B1 (es) 2003-05-08 2007-03-01 Universidad De Zaragoza. Uso de anticuerpos para el tratamiento de enfermedades amiloideas.
EP1480041A1 (fr) 2003-05-22 2004-11-24 Innogenetics N.V. Méthode de prédiction, diagnostic et diagnostic différential de la maladie d'Alzheimer
WO2005018536A2 (fr) 2003-05-23 2005-03-03 Human Genome Sciences, Inc. Anticorps agonistes de liaison specifique au recepteur de peptide 1 assimile au glucagon
PE20050627A1 (es) 2003-05-30 2005-08-10 Wyeth Corp Anticuerpos humanizados que reconocen el peptido beta amiloideo
CA2528182A1 (fr) 2003-06-06 2005-06-16 Oncomax Acquisition Corp. Anticorps specifiques de l'antigene sm5-1 associe au cancer et utilisations associees
US7892751B2 (en) 2003-06-09 2011-02-22 Redox-Reactive Reagents Llc Method of detecting or diagnosing of a neurodegenerative disease or condition
JP4888876B2 (ja) 2003-06-13 2012-02-29 田平 武 アルツハイマー病の治療のための組換えアデノ随伴ウィルスベクター
KR20060022289A (ko) 2003-06-23 2006-03-09 제네틱스 인스티튜트, 엘엘씨 인터류킨-22 에 대한 항체 및 그의 용도
US20050009110A1 (en) 2003-07-08 2005-01-13 Xiao-Jia Chang Methods of producing antibodies for diagnostics and therapeutics
JP4788999B2 (ja) 2003-07-15 2011-10-05 小野薬品工業株式会社 分枝鎖カルボン酸化合物およびその用途
WO2005012330A2 (fr) 2003-07-30 2005-02-10 Brigham And Women's Hospital, Inc. Peptide $g(b)-amyloide et procedes pour l'utiliser
WO2005011599A2 (fr) 2003-08-01 2005-02-10 Northwestern University Anticorps specifiques des oligomeres a proteines beta amyloides toxiques
WO2005014618A2 (fr) 2003-08-08 2005-02-17 Immunomedics, Inc. Anticorps bispecifiques pour induire l'apoptose de cellules tumorales et malades
JP4239750B2 (ja) 2003-08-13 2009-03-18 セイコーエプソン株式会社 マイクロレンズ及びマイクロレンズの製造方法、光学装置、光伝送装置、レーザプリンタ用ヘッド、並びにレーザプリンタ
WO2005018424A2 (fr) 2003-08-18 2005-03-03 Research Foundation For Mental Hygiene, Inc. Anticorps specifiques de la proteine amyloide fibrillaire et procedure permettant de detecter des depots de proteines amyloides fibrillaires
US20050042664A1 (en) 2003-08-22 2005-02-24 Medimmune, Inc. Humanization of antibodies
US20070031416A1 (en) 2003-09-09 2007-02-08 Takeda Pharmaceutical Company Limited Use of antibody
US20070110750A1 (en) 2003-09-12 2007-05-17 The Regents Of The University Of California Monoclonal antibodies specific for high molecular weight aggregation intermediates common to amyloids formed from proteins of differing sequence
EP1516930A1 (fr) 2003-09-16 2005-03-23 Georg-August Universität Göttingen Modèle cellulaire des tauopathies pour identifier "lead" et découvrir des médicaments
EP1670510A1 (fr) 2003-09-24 2006-06-21 Peter Krammer Anticorps diriges contre les annexines, leur utilisation a des fins therapeutiques et diagnostiques, utilisation des annexines a des fins therapeutiques et diagnostiques
IL158287A0 (en) 2003-10-07 2004-05-12 Yeda Res & Dev Antibodies to nik, their preparation and use
AU2004278175B2 (en) 2003-10-07 2010-11-04 Yeda Research And Development Co. Ltd. Antibodies to NIK, their preparation and use
US20070015218A1 (en) 2003-10-14 2007-01-18 University Of South Florida A Method for the Separation Anti-Amyloid Beta Antibody with Amyloid Beta Peptide
EP2071333B1 (fr) 2003-10-15 2012-04-18 Sekisui Medical Co., Ltd. Procédé d'analyse sélective de multimers d'adiponectine
CA2543058A1 (fr) 2003-10-20 2005-05-12 Envivo Pharmaceuticals, Inc. Mouches transgeniques exprimant un mutant a.beta.42
JP2007535906A (ja) 2003-10-24 2007-12-13 イステイチユート・デイ・リチエルケ・デイ・ビオロジア・モレコラーレ・ピ・アンジエレツテイ・エツセ・ピー・アー 直交遺伝子スイッチ
PT1682180E (pt) 2003-11-04 2010-02-10 Novartis Vaccines & Diagnostic Anticorpos monoclonais antagonistas anti-cd40 e métodos para a sua utilização
US7807777B2 (en) 2003-11-05 2010-10-05 Immuno-Biological Laboratories Co., Ltd. Marker peptide for alzheimer's disease
EP1694816B1 (fr) 2003-11-07 2013-08-28 Ciphergen Biosystems, Inc. Biomarqueurs pour la maladie d'alzheimer
US20070264280A1 (en) 2003-11-07 2007-11-15 Federoff Howard J Compositions and Methods for Treating Neurological Diseases
US7674599B2 (en) 2003-11-08 2010-03-09 Elan Pharmaceuticals, Inc. Methods of using antibodies to detect alpha-synuclein in fluid samples
KR100556660B1 (ko) 2003-11-11 2006-03-10 국립암센터 Hgf의 중화가능 에피토프 및 이에 결합하는 중화 항체
US20050226863A1 (en) 2003-11-20 2005-10-13 Massachusetts Institute Of Technology Single-domain antibodies and uses thereof
WO2005051998A2 (fr) 2003-11-28 2005-06-09 Astrazeneca Ab Anticorps
JP4870348B2 (ja) 2003-12-04 2012-02-08 株式会社ペルセウスプロテオミクス 細胞表面抗原に対する抗体取得とその抗原同定
EP2865687A1 (fr) 2003-12-10 2015-04-29 E. R. Squibb & Sons, L.L.C. Anticorps IP-10 et leurs utilisations
UA93854C2 (ru) 2003-12-17 2011-03-25 Вайет Ллк Иммуногенный конъюгат и способ его получения
BRPI0417959A (pt) 2003-12-22 2007-03-27 Glaxo Group Ltd anticorpo ou fragmento funcional deste, composição farmcêutica, método para tratamento ou profilaxia de acidente vascular cerebral e outras doenças/distúrbios neurológicos em um ser humano, uso de um anticorpo anti-nogo, e, métodos para inibir a neurodegeneração e/ou promover a recuperação funcional em um paciente humano, para promover o crescimento axonal, para produzir um anticorpo anti-nogo e para produzir uma composição farmacêutica intravenosamente administrável
WO2005070965A2 (fr) 2004-01-21 2005-08-04 Five Prime Therapeutics, Inc. Compositions pharmaceutiques contenant des antagonistes a lrp4, lrp8 ou a la megaline pour le traitement de maladies
US20070172496A1 (en) 2004-01-28 2007-07-26 Curix Aps Conjugates of amyloid proteins as vaccines for amyloid-related diseases
US7238788B2 (en) 2004-02-18 2007-07-03 University Of Iowa Foundation Antibodies to phosphorylated tau, methods of making and methods of use
US7807157B2 (en) 2004-02-20 2010-10-05 Intellect Neurosciences Inc. Monoclonal antibodies and use thereof
US20070190046A1 (en) 2004-02-23 2007-08-16 Eli Lilly And Company Anti-abeta antibody
WO2005105841A2 (fr) 2004-03-12 2005-11-10 Human Genome Sciences, Inc. Récepteur humain (ccr5) hdgnr10 de chimiokine de la protéine g
US20080057057A1 (en) 2004-03-18 2008-03-06 Applied Research Systems Ars Holding N.V. Anti-Lipid Rafts Antibodies
CN1314805C (zh) 2004-03-26 2007-05-09 中国人民解放军军事医学科学院放射与辐射医学研究所 一种新型促细胞凋亡素(apo)及其抗体,制备及用途
SI1730191T1 (sl) 2004-03-30 2011-11-30 Glaxo Group Ltd Imunoglobulin-vezavni hOSM
JP2008502880A (ja) 2004-04-02 2008-01-31 メルク エンド カムパニー インコーポレーテッド アミロイド前駆体タンパク質又はβアミロイド断片に結合する物質を検出する方法及び結合化合物
US20060099211A1 (en) 2004-04-12 2006-05-11 Carmen Monthe Safer, more potent human immunoglobulin preparations for treating Alzheimer's disease
JP2007535317A (ja) 2004-04-15 2007-12-06 グライコフィ, インコーポレイテッド 下等真核生物におけるガラクトシル化された糖タンパク質の産生
EP1755605A2 (fr) 2004-04-15 2007-02-28 Samaritan Pharmaceuticals, Inc. Utilisation des (2-alkylpiperazinyl) (phenyl) methanones dans le traitement de la maladie d'alzheimer
US7763249B2 (en) 2004-04-27 2010-07-27 Juridical Foundation The Chemo-Sero-Therapeutic Research Institute Human anti-amyloid β peptide antibody and fragment of said antibody
ITRM20040212A1 (it) 2004-04-30 2004-07-30 Lay Line Genomics Spa Animale transgenico non umano come modello per malattie neurodegenerative e per la loro diagnosi precoce.
GR1005016B (el) 2004-05-14 2005-10-11 BIOMENTIKA@ΛΑΙΦ@ΣΑΙΕΝΣΙΣ@ΑΝΩΝΥΜΗ@ΕΤΑΙΡΕΙΑ@ΦΑΡΜΑΚΕΥΑΤΙΚΩΝ@ΠΡΟΙΟΝΤΩΝ@(συμμετέχει@σε@ποσοστό@50%)@Α ΑΝΑΠΤΥΞΗ ΑΝΤΙΣΩΜΑΤΩΝ IgG KAI IgY ΕΝΑΝΤΙΟΝ ΕΙΔΙΚΟΥ ΣΥΝΘΕΤΙΚΟΥ ΕΠΙΤΟΠΙΚΟΥ ΠΑΡΑΓΩΓΟΥ ΤΗΣ HUMANIN (24-ΠΕΠΤΙΔΙΟΥ ΣΧΕΤΙΖΟΜΕΝΟΥ ΜΕ ΤΗ ΝΟΣΟ ALZHEIMER) ΙΚΑΝΩΝ ΝΑ ΑΝΙΧΝΕΥΟΥΝ ΤΟ ΒΙΟΔΡΑΣΤΙΚΟ 24-ΠΕΠΤΙΔΙΟ.
JP2008500286A (ja) 2004-05-14 2008-01-10 ノースウエスタン ユニバーシティ Addl受容体を含む組成物、関連する組成物、および関連する方法
ATE476993T1 (de) 2004-06-07 2010-08-15 Univ Ramot Verfahren zur passiven immunisierung gegen eine durch amyloidaggregation gekennzeichnete krankheit oder erkrankung mit vermindertem nervenentzündungsrisiko
WO2005123776A1 (fr) 2004-06-10 2005-12-29 Omeros Corporation Procédés servant à traiter des affections associées à l'activation du complément dépendant de la lectine
US20050276806A1 (en) 2004-06-15 2005-12-15 Advanced Biotherapy, Inc. Treatment of autism
EP1877082A2 (fr) 2004-06-18 2008-01-16 The Government of the United States of America as represented by The Secretary of the Department of Health and Human Services Preparation des globulines anti-lymphocytic et anti-monocytic pour empecher des immuno-reactions
SE0401601D0 (sv) 2004-06-21 2004-06-21 Bioarctic Neuroscience Ab Protofibril specific antibodies and uses thereof
JP2008513732A (ja) 2004-07-02 2008-05-01 ノースウエスタン ユニバーシティ アミロイドβ(Abeta)の病理学的なアセンブリを標的とするモノクローナル抗体
WO2006005588A1 (fr) 2004-07-12 2006-01-19 Geneprot, Inc. Especes de polypeptide convenant pour le traitement de troubles neurologiques
AT413946B (de) 2004-07-13 2006-07-15 Mattner Frank Dr Impfstoff gegen die alzheimer-krankheit
CN1721437A (zh) 2004-07-13 2006-01-18 中南大学 一种与Tau蛋白相关的多肽抗原及抗体
AT500483B1 (de) 2004-07-13 2006-01-15 Mattner Frank Dr Set zur vorbeugung oder behandlung der alzheimer'schen erkrankung
WO2006006172A2 (fr) 2004-07-15 2006-01-19 Ramot At Tel Aviv University Ltd. Utilisation d'agents anti-amyloides pour traiter et determiner des infections pathogenes
US7955812B2 (en) 2004-07-19 2011-06-07 The General Hospital Corporation Methods of diagnosing alzheimer's disease by detecting antibodies to cross-linked β-amyloid oligomers
MX2007001102A (es) 2004-07-28 2007-04-13 Schering Corp Inhibidores macrociclicos de beta-secretasa.
SG190665A1 (en) 2004-07-30 2013-06-28 Rinat Neuroscience Corp Antibodies directed against amyloid-beta peptide and methods using same
US20070298029A1 (en) 2004-08-09 2007-12-27 Carsten Hopf Treatment of Neurodegenerative Diseases by the Use of Degs Inhibitors
JP2008508893A (ja) 2004-08-11 2008-03-27 エボテツク・ニユーロサイエンシーズ・ゲー・エム・ベー・ハー 形質膜atpアーゼの診断及び治療への使用
EP1787998A4 (fr) 2004-08-11 2008-08-27 Mitsubishi Chem Corp Anticorps et utilisation s'y rapportant
DE102004039326A1 (de) 2004-08-12 2006-02-16 Abbott Gmbh & Co. Kg Neue medizinische Verwendungen und Verfahren
US7335491B2 (en) 2004-08-27 2008-02-26 Wyeth Research Ireland Limited Production of anti-abeta
US20060246075A1 (en) 2004-09-29 2006-11-02 Marc Mercken Anti-amyloid antibodies, compositions, methods and uses
WO2006039327A2 (fr) 2004-10-01 2006-04-13 Merck & Co., Inc. Procedes de traitement ou prophylaxie de maladies amyloidogeniques de l'oeil ou du nerf optique
US7910100B2 (en) 2004-10-01 2011-03-22 Max-Planck-Gesellschaft zur Forderung der Wissen Antibodies directed to the mammalian EAG1 ion channel protein
EA200700751A1 (ru) 2004-10-05 2008-06-30 Элан Фарма Интернэшнл Лимитед Способы и композиции для улучшения продуцирования рекомбинантного белка
ZA200702869B (en) 2004-10-06 2008-07-30 Mori Hiroshi Mutated amyloid protein
JP5113523B2 (ja) 2004-10-13 2013-01-09 アブリンクス ナームローゼ フェンノートシャップ アミロイド−βに対するナノ抗体及びアルツハイマー病のような神経変性疾患の治療のためのナノ抗体TMを含むポリペプチド
WO2006047254A1 (fr) 2004-10-22 2006-05-04 Regents Of The University Of Minnesota Ensembles de proteines beta-amyloides oligomeres et utilisations de ceux-ci
EP2465872A3 (fr) 2004-10-25 2012-12-19 Merck Sharp & Dohme Corporation Anticorps anti-ADDL et leurs utilisations
WO2006047670A2 (fr) 2004-10-26 2006-05-04 Wyeth Procedes permettant d'evaluer les anticorps diriges contre des antigenes associes aux maladies neurodegeneratives
WO2006050041A2 (fr) 2004-10-28 2006-05-11 Ramot At Tel Aviv University Ltd. Procedes pour reduire ou inhiber une inflammation cerebrale ou pour promouvoir une neurogenese
CA2585148A1 (fr) 2004-10-28 2006-05-04 Sanko Junyaku Co., Ltd. Procede d'examen de la maladie d'alzheimer et reactif de diagnostic
JP2008519284A (ja) 2004-11-08 2008-06-05 ナノバック ファーマシューティカルズ, インコーポレイテッド タンパク質−ヒドロキシアパタイト複合体に関する方法および組成物、ならびにカルシウム結合タンパク質−ヒドロキシアパタイト複合体に対する抗体の検出のための新規インビトロ試験を含む免疫系を試験および調節することにおけるそれらの適用
US7709208B2 (en) 2004-11-08 2010-05-04 New York University Methods for diagnosis of major depressive disorder
CN1772766A (zh) 2004-11-12 2006-05-17 中国科学院上海生命科学研究院 抗细胞凋亡相关乙酰胆碱酯酶单克隆抗体及其用途
EP2186518A1 (fr) 2004-11-17 2010-05-19 McLaurin, Joanne Préparations comprenant des dérivés de scyllo-inositol et méthodes de traitement de troubles d'agrégation protéinique
US8916165B2 (en) 2004-12-15 2014-12-23 Janssen Alzheimer Immunotherapy Humanized Aβ antibodies for use in improving cognition
US7625560B2 (en) 2004-12-15 2009-12-01 Janssen Alzheimer Immunotherapy Humanized antibodies that recognize beta amyloid peptide
WO2006066118A2 (fr) 2004-12-15 2006-06-22 Neuralab Limited Conditionnement contextuel des peurs pour predire l'efficacite immunotherapeutique
US20060240486A1 (en) 2004-12-15 2006-10-26 Johnson-Wood Kelly L Immunoprecipitation-based assay for predicting in vivo efficacy of beta-amyloid antibodies
PE20061401A1 (es) 2004-12-15 2006-12-23 Neuralab Ltd ANTICUERPOS Aß PARA MEJORAR LA COGNICION
JP2006166879A (ja) 2004-12-20 2006-06-29 Japan Health Science Foundation Ab−dip、並びにアルツハイマー病の予防及び治療剤
MY146381A (en) 2004-12-22 2012-08-15 Amgen Inc Compositions and methods relating relating to anti-igf-1 receptor antibodies
WO2006067792A2 (fr) 2004-12-22 2006-06-29 Yeda Research And Development Co. Ltd. At The Weizmann Institute Of Science Autoantigenes de l'aldolase utiles pour le diagnostic et le traitement de la maladie d'alzheimer
EP1827493A4 (fr) 2004-12-22 2009-09-30 Univ St Louis Utilisation d'anticorps anti-abeta pour le traitement d'un traumatisme cerebral
EP1676859A1 (fr) 2004-12-30 2006-07-05 Pevion Biotech Ltd. Compositions immunogènes contenant des peptides cycliques derivés du peptide beta-amyloide
US20110020237A1 (en) 2005-01-14 2011-01-27 Glabe Charles G Compositions and Methods for Inhibiting Drusen Formation and for Diagnosing or Treating Drusen-Related Disorders
AU2006208226A1 (en) 2005-01-24 2006-08-03 Amgen Inc. Humanized anti-amyloid antibody
GT200600031A (es) 2005-01-28 2006-08-29 Formulacion anticuerpo anti a beta
JP2006213621A (ja) 2005-02-02 2006-08-17 Japan Health Science Foundation Adoplinタンパク質、およびその利用
US20070082350A1 (en) 2005-02-09 2007-04-12 Philip Landfield Assay and method for diagnosing and treating alzheimer's disease
US7700099B2 (en) 2005-02-14 2010-04-20 Merck & Co., Inc. Non-immunostimulatory antibody and compositions containing the same
US7731962B2 (en) 2005-02-14 2010-06-08 Merck & Co., Inc. Anti-ADDL monoclonal antibody and use thereof
GB0503434D0 (en) 2005-02-18 2005-03-30 Senexis Ltd Amyloid-binding peptides, analogues and uses thereof
BRPI0607486B8 (pt) 2005-03-03 2021-05-25 Immunomedics Inc anticorpo humanizado l243 contra hla-dr presente nas células hladr+,composição farmacêutica, kit e uso dos referidos anticorpos.
CN101171263A (zh) 2005-03-04 2008-04-30 比奥根艾迪克Ma公司 通过合理修饰互补决定区残基使免疫球蛋白可变区人源化的方法
EP1861422B1 (fr) 2005-03-05 2010-02-24 Abbott GmbH & Co. KG Methode de criblage, procede servant a purifier des a-beta oligomeres non diffusibles, anticorps selectifs contre les dits a-beta oligomeres non diffusibles et procede servant a preparer ces anticorps
US20080152644A1 (en) 2005-03-07 2008-06-26 Ho-Juhn Song Genes Involved in Neurodegenerative Conditions
ES2259270B1 (es) 2005-03-09 2007-11-01 Consejo Superior De Investigaciones Cientificas Metodo de diagnostico in vitro de la enfermedad de alzheimer mediante un anticuerpo monoclonal.
WO2006099543A2 (fr) 2005-03-15 2006-09-21 The Regents Of The University Of California Methodes d'evaluation de la toxicite induite par des anticorps
WO2006100679A2 (fr) 2005-03-22 2006-09-28 Quark Pharmaceuticals, Inc. Anticorps de recombinaison diriges contre la transglutaminase humaine de type ii et utilisations de ces anticorps
JP2006265189A (ja) 2005-03-24 2006-10-05 Kyoto Univ βアミロイドペプチド、及びそれを用いたアルツハイマー病治療薬又は予防薬のスクリーニング方法
ES2318918B1 (es) 2005-04-01 2010-02-16 Biotherapix Molecular Medicines, S.L.U. Anticuerpos humanos con capacidad de union al peptido beta-amiloide y sus aplicaciones.
US8227194B2 (en) 2005-04-08 2012-07-24 University Of Maryland, Baltimore Monoclonal antibodies with binding specificity for response gene to complement 32 (RGC-32)
US20060241038A1 (en) 2005-04-20 2006-10-26 Eisai Co., Ltd. Therapeutic agent for Abeta related disorders
ZA200708857B (en) 2005-04-22 2009-01-28 Genentech Inc Method for treating dementia or alzheimer's disease with a CD30 antibody
MY148086A (en) 2005-04-29 2013-02-28 Rinat Neuroscience Corp Antibodies directed against amyloid-beta peptide and methods using same
WO2006119449A2 (fr) 2005-05-04 2006-11-09 Vectorlogics, Inc. Adenovirus modifie contenant un anticorps stabilise
EP1879613B1 (fr) 2005-05-05 2011-11-30 Merck Sharp & Dohme Corp. Compositions à base de conjugués peptidiques et méthodes destinées à la prévention et au traitement de la maladie d'alzheimer
ATE530667T1 (de) 2005-05-27 2011-11-15 Evotec Neurosciences Gmbh Kcnn3 als diagnostisches und therapeutisches target für alzheimer-krankheit
US20060272038A1 (en) 2005-05-27 2006-11-30 Michael De Vivo Transgenic Alzheimer's mouse model vectors and uses thereof
CA2610771A1 (fr) 2005-06-06 2006-12-14 Wyeth Anticorps monoclonaux anti-trkb et utilisations de ceux-ci
EP1896504B1 (fr) 2005-06-17 2012-11-21 Wyeth LLC Procedes de purification des anticorps contenant la region fc
US7741448B2 (en) 2005-06-21 2010-06-22 Medical & Biological Laboratories Co., Ltd. Antibody having inhibitory effect on amyloid fibril formation
TW200726482A (en) 2005-06-30 2007-07-16 Merck & Co Inc Method for preparing a covalently cross linked oligomer of amyloid beta peptides
TW200726774A (en) 2005-06-30 2007-07-16 Merck & Co Inc Composition and method for producing stable amyloid beta oligomers
RS53058B (en) 2005-07-08 2014-04-30 Biogen Idec Ma Inc. SP35 ANTIBODIES AND THEIR APPLICATIONS
JP5102205B2 (ja) 2005-07-13 2012-12-19 コイミュン インコーポレイテッド 触媒免疫グロブリン
WO2007011834A2 (fr) 2005-07-15 2007-01-25 The Regents Of The University Of California Composes et procede pour diagnostiquer et traiter les maladies associees aux amyloides
CA2618508A1 (fr) 2005-08-10 2007-02-22 Oklahoma Medical Research Foundation Compositions de memapsine 2 tronquee et traitements associes
GB2429013C (en) 2005-08-11 2012-11-28 Arpi Matossian-Rogers Peptides for treatment and diagnosis of autoimmunedisease
KR20080068004A (ko) 2005-08-15 2008-07-22 아라나 테라퓨틱스 리미티드 뉴 월드 영장류 구조형성영역을 가진 조작 항체
US8124076B2 (en) 2005-08-18 2012-02-28 Ramot At Tel Aviv University Ltd. Single chain antibodies against β-amyloid peptide
US7612181B2 (en) 2005-08-19 2009-11-03 Abbott Laboratories Dual variable domain immunoglobulin and uses thereof
JP2007077103A (ja) 2005-09-16 2007-03-29 Yokohama City Univ アルツハイマー病の予防又は治療剤
EP1934341A1 (fr) 2005-10-03 2008-06-25 AstraZeneca AB Proteines de fusion ayant une demi-vie modulee dans du plasma
CA2625440C (fr) 2005-10-11 2023-06-13 Micromet Ag Compositions comportant des anticorps specifiques d'especes croisees et leurs utilisations
EP1940466B1 (fr) 2005-10-21 2012-11-28 Merck Sharp & Dohme Corp. Anticorps monoclonaux anti-addl et leur utilisation
US20070092508A1 (en) 2005-10-21 2007-04-26 Recombiant Technologies, Llc Detoxification depot for Alzheimer's disease
AU2006304804B2 (en) 2005-10-21 2011-06-02 Vertex Pharmaceuticals Incorporated Modified proteases that inhibit complement activation
US20090202531A1 (en) 2005-11-01 2009-08-13 Novartis Ag Uses of anti-cd40 antibodies
US20090181008A1 (en) 2005-11-10 2009-07-16 Satoris, Inc. Methods of treating alzheimer's disease
US8316104B2 (en) 2005-11-15 2012-11-20 California Institute Of Technology Method and apparatus for collaborative system
US20080014596A1 (en) 2005-11-16 2008-01-17 Jasna Jerecic ADDL Binding to Hippocampal Neurons
US9133267B2 (en) 2005-11-22 2015-09-15 The Trustees Of The University Of Pennsylvania Antibody treatment of Alzheimer's and related diseases
JP2009518010A (ja) 2005-11-30 2009-05-07 アボット・ラボラトリーズ ヒトβアミロイドタンパク質の組み換え形態の調製方法及びこれらのタンパク質の使用
CN102898519B (zh) 2005-11-30 2015-10-28 Abbvie公司 抗淀粉样β蛋白的单克隆抗体及其用途
PL2289909T3 (pl) 2005-11-30 2015-04-30 Abbvie Inc Sposób przeszukiwania, proces oczyszczania niedyfundujących oligomerów Abeta, selektywne przeciwciała przeciw niedyfundującym oligomerom Abeta i sposób wytwarzania tych przeciwciał
US20070237764A1 (en) 2005-12-02 2007-10-11 Genentech, Inc. Binding polypeptides with restricted diversity sequences
WO2007067512A2 (fr) 2005-12-08 2007-06-14 Merck & Co., Inc. Procede pour identifier des modulateurs d'adprh convenant pour traiter la maladie d'alzheimer
RS52004B (en) 2005-12-12 2012-04-30 F. Hoffmann-La Roche Ag ANTIBODIES AGAINST AMYLOID BETA WITH GLYCOSILATION IN THE VARIABLE REGION
KR101505201B1 (ko) 2005-12-12 2015-03-24 에이씨 이뮨 에스.에이. 치료적 특성을 갖는 베타 1-42 특이적인 단일클론성 항체
AU2006326283B2 (en) 2005-12-12 2012-01-19 Ac Immune S.A. Therapeutic vaccine
JP5358187B2 (ja) 2005-12-15 2013-12-04 ジェネンテック, インコーポレイテッド ポリユビキチンを標的とする方法と組成物
US20080058276A1 (en) 2006-01-13 2008-03-06 Cornell Research Foundation, Inc. Alzheimer's disease therapeutics based on pin-1 catalyzed conformational changes in phosphorylated amyloid precursor protein
EP1811304A1 (fr) 2006-01-18 2007-07-25 Friedrich-Alexander-Universität Erlangen-Nürnberg Grandes particules de liaison de peptide Aß (LAPS) dans le diagnostic et la thérapie de la maladie d'Alzheimer
CN1329413C (zh) 2006-01-23 2007-08-01 南京医科大学 一种治疗或预防老年性痴呆的抗体及其表达载体和在制药中的应用
PT1981540E (pt) 2006-01-30 2013-05-07 Grifols Therapeutics Inc Método de tratamento e profilaxia de doenças relacionadas com a deposição de amilóides utilizando igm
GB0601976D0 (en) 2006-02-01 2006-03-15 Merck Sharp & Dohme Proteins
US20090304712A1 (en) 2006-02-02 2009-12-10 National University Corporation Nagoya University Neuronal Cell Death Inhibitor and Screening Method
EP1984396A2 (fr) 2006-02-06 2008-10-29 Elan Pharmaceuticals Inc. Inhibiteurs specifiques de la preseniline-i et leur utilisation
JP2009526020A (ja) 2006-02-09 2009-07-16 ノバルティス アクチエンゲゼルシャフト 分泌型frizzled関連タンパク質4(SFRP−4)タンパク質結合剤
CA2643048A1 (fr) 2006-02-21 2007-08-30 Oklahoma Medical Research Foundation Traitement de la maladie d'alzheimer avec des inhibiteurs de la fixation de l'apoe au recepteur de l'apoe
US20070196367A1 (en) 2006-02-22 2007-08-23 Valentin Dinu Methods of preventing and treating Alzheimer's disease, age related macular degeneration and other diseases involving extra-cellular debris through the inhibition of the complement system
WO2007097251A1 (fr) 2006-02-22 2007-08-30 Kabushiki Kaisha Hayashibara Seibutsu Kagaku Kenkyujo VACCIN PEPTIDIQUE DESTINE A INDUIRE LA PRODUCTION D'ANTICORPS ANTI-PEPTIDE AMYLOIDE β
ZA200807228B (en) 2006-02-24 2009-11-25 Chiesi Farma Spa Anti-amyloid immunogenic compositions, methods and uses
US20100196932A1 (en) 2006-03-02 2010-08-05 The Board Of Trustees Of The University Of Illinois Yeast Reporter System
JP5823663B2 (ja) 2006-03-03 2015-11-25 プロミス ニューロサイエンシズ インコーポレイテッド ミスフォールドsod1媒介疾患を処置および検出するための方法および組成物
WO2007109107A2 (fr) 2006-03-17 2007-09-27 The Trustees Of Columbia University In The City Of New York Atf4 utilisé comme cible thérapeutique dans la maladie d'alzheimer et autres troubles neurologiques
BRPI0708970A2 (pt) 2006-03-21 2011-06-21 Wyeth Corp método para o tratamento de um sujeito com uma doença ou transtorno caracterizado por depósito amilóide de a-beta; método de inibição ou redução da acumulação de depósito amilóide de a-beta em um sujeito; método de inibição ou redução da neurodegeneração em um sujeito; e método de inibição ou redução do declìnio cognitivo, ou de melhora da cognição, em um sujeito
WO2007112288A2 (fr) 2006-03-23 2007-10-04 Mount Sinai School Of Medicine Composition cardiovasculaire et utilisation de ladite composition pour le traitement de la maladie d'alzheimer
EP2325209A3 (fr) 2006-03-23 2011-08-03 BioArtic Neuroscience AB Anticorps améliorés sélectifs de protofibrilles et leur utilisation
CA2541522A1 (fr) 2006-03-28 2007-09-28 E. Rick Preddie Dosage immunoenzymatique double pour detecter la maladie de l'alzheimer avec applications pour des vaccins therapeutiques visant a enrayer la maladie
PL2177536T3 (pl) 2006-03-30 2014-11-28 Glaxo Group Ltd Przeciwciała przeciwko peptydowi beta-amyloidu
FR2899107B1 (fr) 2006-03-30 2008-06-13 Neurokin Entpr Unipersonnelle Utilisation de la (s)-roscovitine pour la fabrication d'un medicament
WO2007123680A2 (fr) 2006-03-31 2007-11-01 The Regents Of The University Of California Procédés et compositions pour traiter des maladies neurodégénératives, en particulier la maladie d'alzheimer, et améliorer la mémoire normale
JP4790013B2 (ja) 2006-04-13 2011-10-12 エーディア株式会社 β−アミロイドの血中分解速度測定によるアルツハイマー病の検定に用いられる方法及び診断試薬
CN101058608B (zh) 2006-04-21 2011-02-23 杜如昱 人类抗Aβ1-32淀粉样蛋白抗体、其纯化方法及用途
CA2649359A1 (fr) 2006-04-21 2007-11-01 Peoplebio, Inc. Procede de detection differentielle d'une forme multimere et d'une forme monomere dans des polypeptides formant des multimeres par interactions tridimensionnelles
JP5311303B2 (ja) 2006-04-25 2013-10-09 国立大学法人 東京大学 アルツハイマー病および癌の治療薬
CA2650376A1 (fr) 2006-04-27 2007-11-08 The Mclean Hospital Corporation Methodes de traitement et de criblage servant a promouvoir la neurogenese
GB0608386D0 (en) 2006-04-27 2006-06-07 Senexis Ltd Compounds
CA2650704A1 (fr) 2006-04-28 2007-11-08 Northwestern University Sels de composes de pyridazine
JP2007300856A (ja) 2006-05-11 2007-11-22 Hiroshi Mori アミロイドタンパク質模倣物
US20070292895A1 (en) 2006-05-19 2007-12-20 Xiao-Ping Shi Assays and methods to detect beta-secretase and its activity in body fluids and tissue extracts
JP2009538924A (ja) 2006-06-01 2009-11-12 エラン ファーマシューティカルズ,インコーポレイテッド Appの神経活性断片
US7427342B2 (en) 2006-06-02 2008-09-23 General Electric Company Method and apparatus for shifting current distribution in electrodeionization systems
JP4933159B2 (ja) 2006-06-02 2012-05-16 国立大学法人金沢大学 アルツハイマー病の診断方法
US7479550B2 (en) 2006-06-02 2009-01-20 The Board Of Regents Of The University Of Texas System Amyloid β gene vaccines
WO2007144198A2 (fr) 2006-06-16 2007-12-21 Umc Utrecht Holding B.V. INHIBITEURS DU FPLR-1 (FLIPr ET TYPE FLIPr) À UTILISER DANS DES MALADIES IMPLIQUANT DES ÉPISODES INFLAMMATOIRES INDUITS PAR LES AMYLOÏDES ET DES MALADIES MÉDIÉES PAR LE COMPLEXE IMMUNITAIRE
TW200815469A (en) 2006-06-23 2008-04-01 Astrazeneca Ab Compounds
WO2008002893A2 (fr) 2006-06-29 2008-01-03 Centocor, Inc. Anticorps anti-amyloïdes, compositions, procédés et utilisations
US20080058330A1 (en) 2006-07-06 2008-03-06 Roskamp Research Llc Compounds and Combinations Thereof for Inhibiting Beta-Amyloid Production and Methods of Use Thereof
JP2009544158A (ja) 2006-07-13 2009-12-10 パーカー.ハニフィン.コーポレイション 電磁障害吸収用填隙性材料
CL2007002070A1 (es) 2006-07-14 2008-02-08 Ac Immune S A Genentech Inc Anticuerpo quimerico o humanizado, o fragmentos de ellos, que se adhieren especificamente a por lo menos un epitopo en la proteina beta-amiloide; molecula de acido nucleico que lo codifica; composicion que lo comprende; su uso para tratar enfermedade
WO2008008463A2 (fr) 2006-07-14 2008-01-17 Trustees Of Columbia University In The City Of New York PROCÉDÉS ET COMPOSITIONS SERVANT À DÉTECTER ET QUANTIFIER sAPPβ
ATE426174T1 (de) 2006-07-28 2009-04-15 Vista Ventures Gmbh Verfahren zum nachweis der amyloid-beta oligomere in kírperflussigkeiten
US7705475B2 (en) 2006-08-03 2010-04-27 Stats Chippac Ltd. Integrated circuit package system
EP2047393A1 (fr) 2006-08-04 2009-04-15 Lonza Biologics plc. Procédé permettant de prédire l'agrégation d'une protéine et de concevoir des inhibiteurs d'agrégation
WO2008021296A2 (fr) 2006-08-14 2008-02-21 Thymon, L.L.C. Compositions et méthodes pour le traitement et la prévention de la maladie d'alzheimer
AU2007285763B2 (en) 2006-08-18 2011-12-15 Armagen Technologies, Inc. Agents for blood-brain barrier delivery
WO2008051326A2 (fr) 2006-08-21 2008-05-02 President And Fellows Of Harvard College Identification de contactines et de cams l1 en tant que ligands pour la protéine précurseur amyloïde
WO2008070229A2 (fr) 2006-08-28 2008-06-12 Case Western Reserve University Détection d'agrégats pathogènes de protéine dans un échantillon par elisa homologue
US8372399B2 (en) 2006-08-31 2013-02-12 Cardiac Pacemakers, Inc. Bispecific antibodies and agents to enhance stem cell homing
JP2010502623A (ja) 2006-08-31 2010-01-28 バイオジェン・アイデック・エムエイ・インコーポレイテッド Nogoレセプターポリペプチドの末梢投与に関する方法
EP2074222A4 (fr) 2006-09-06 2010-03-03 Univ Texas Méthodes et compositions pour la détection de troubles du repliement des protéines
WO2008030251A1 (fr) 2006-09-08 2008-03-13 Georgetown University Anticorps deglycosylés anti-bêta amyloïde
CA2662723A1 (fr) 2006-09-08 2008-03-13 Vib Vzw Moyens et procedes pour la production d'oligomeres amyloides
ES2307396B1 (es) 2006-09-14 2009-09-30 Fundacion Para Investigaciones Neurologicas (Fin) Sistemas de eliminacion de sustancias neurotoxicas causantes de enfermedades neurodegenerativas mediante su atrapamiento selectivo por inmunoafinidad en el liquido cefalo-raquideo circulante.
US7375190B2 (en) 2006-09-19 2008-05-20 National Yang-Ming University Recombinant protein and method of screening for agents that modulate polypeptide aggregation
CN101611054B (zh) 2006-10-02 2013-12-25 Ac免疫有限公司 针对淀粉状蛋白β的人源化抗体
US9382327B2 (en) 2006-10-10 2016-07-05 Vaccinex, Inc. Anti-CD20 antibodies and methods of use
US20100104577A1 (en) 2006-10-10 2010-04-29 Golde Todd E Methods and materials related to anti-a (beta) antibodies
JP5153114B2 (ja) 2006-10-12 2013-02-27 知宏 千葉 新規のアルツハイマー病検出方法
US20080113444A1 (en) 2006-10-17 2008-05-15 Pray Todd R Method for detecting oligermization of soluble amyloid beta oligomers
GB0620735D0 (en) 2006-10-18 2006-11-29 Ares Trading Sa Proteins
KR100883132B1 (ko) 2006-10-24 2009-02-10 재단법인서울대학교산학협력재단 아밀로이드 형성 펩타이드 또는 단백질의 가용성 회합체에선택적으로 작용하는 절단제
WO2008057240A2 (fr) 2006-10-27 2008-05-15 Abbott Biotechnology Ltd. Anticorps anti-htnfalpha cristallisés
WO2008130449A2 (fr) 2006-11-20 2008-10-30 Satori Pharmaceuticals, Inc. Modulateurs de la production de bêta-amyloïde
WO2008064244A2 (fr) 2006-11-20 2008-05-29 The Trustees Of Columbia University In The City Of New York Modulation des phosphoinositides pour le traitement de maladies neurodégénératives
US20100183513A1 (en) 2006-11-24 2010-07-22 Wolfgang Froestl N-(methyl) -1h-pyrazol-3-amine, n-(methyl)-pyridin-2-amine and n-(methyl)-thiazol-2-amine derivatives for the treatment of diseases associated with amyloid or amyloid-like proteins, like e.g. alzheimer's
US8455626B2 (en) 2006-11-30 2013-06-04 Abbott Laboratories Aβ conformer selective anti-aβ globulomer monoclonal antibodies
WO2008143708A2 (fr) 2006-12-07 2008-11-27 Mayo Foundation For Medical Education And Research Procédés et matériaux associés à des anticorps anti-amyloïdes
EP2094729A1 (fr) 2006-12-11 2009-09-02 F.Hoffmann-La Roche Ag Formulation parentérale d'anticorps anti-peptide abêta
WO2008076262A2 (fr) 2006-12-15 2008-06-26 Merck & Co., Inc. Récepteur pour bêta amyloïde et utilisations de celui-ci
AU2008204335B2 (en) 2007-01-11 2013-06-13 Michael Bacher Diagnosis and treatment of Alzheimer's and other neurodementing diseases
WO2008140639A2 (fr) 2007-02-08 2008-11-20 Oligomerix, Inc. Biomarqueurs et dosages pour la maladie d'alzheimer
KR100806914B1 (ko) 2007-02-14 2008-02-22 경북대학교 산학협력단 퇴행성 신경질환의 예방 및 치료를 위한 리포칼린 2의 신규한 용도
US20100311767A1 (en) 2007-02-27 2010-12-09 Abbott Gmbh & Co. Kg Method for the treatment of amyloidoses
EP2125015A1 (fr) 2007-02-27 2009-12-02 Abbott GmbH & Co. KG Méthode de traitement d'amyloïdoses
GB0704394D0 (en) 2007-03-07 2007-04-11 Senexis Ltd Compounds
US20090022728A1 (en) 2007-03-09 2009-01-22 Rinat Neuroscience Corporation Methods of treating ophthalmic diseases
EP1978035A1 (fr) 2007-04-05 2008-10-08 Hans-Knöll-Institut Leibniz-Institut für Naturstoff-Forschung Anticorps anti-amyloïdes et leur utilisation dans le diagnostic et la thérapie des maladies amyloïdes
EP2656839A1 (fr) 2007-04-12 2013-10-30 Waratah Pharmaceuticals, Inc. Utilisation de dérivés de cyclohexanehexol dans le traitement de maladies oculaires
KR20100016661A (ko) 2007-04-18 2010-02-12 얀센 알츠하이머 이뮤노테라피 대뇌 아밀로이드 혈관병증의 예방 및 치료
CA2683053A1 (fr) 2007-04-19 2008-10-30 Vib Vzw Compositions d'oligonucleotides pour le traitement de la maladie d' alzheimer
US9217036B2 (en) 2007-04-26 2015-12-22 Yale University Prion protein as a receptor for amyloid-β oligomers
WO2008150467A1 (fr) 2007-05-30 2008-12-11 The Regents Of The University Of Michigan Essais préliminaires pour des inhibiteurs du canal ionique de peptide bêta-amyloïde
US20090232801A1 (en) 2007-05-30 2009-09-17 Abbot Laboratories Humanized Antibodies Which Bind To AB (1-42) Globulomer And Uses Thereof
US20090175847A1 (en) 2007-05-30 2009-07-09 Abbott Laboratories Humanized antibodies to ab (20-42) globulomer and uses thereof
EP2574345A1 (fr) 2007-06-12 2013-04-03 AC Immune S.A. Anticorps humanisés à amyloïde bêta
NZ601843A (en) 2007-06-12 2014-01-31 Ac Immune Sa Monoclonal anti beta amyloid antibody
EP2009445A1 (fr) 2007-06-29 2008-12-31 Institut Pasteur Utilisation d'anticorps à domaine simple de chaînes pour détecter une formule oligomérique d'un peptide amyloide bêta et ses applications
CN101084909A (zh) 2007-07-03 2007-12-12 福建医科大学附属协和医院 人参皂苷Rg1的新用途
ES2401664T3 (es) 2007-07-12 2013-04-23 Acumen Pharmaceuticals, Inc. Procedimientos de modificación de oligómeros beta amiloides utilizando compuestos no peptídicos
WO2009008891A1 (fr) 2007-07-12 2009-01-15 Acumen Pharmaceuticals, Inc. Procédés d'amélioration de la fonction cognitive en utilisant des composés non peptidiques
EP2194975A2 (fr) 2007-07-12 2010-06-16 Acumen Pharmaceuticals, Inc. PROCÉDÉS CONSISTANT À INHIBER LA FORMATION DE LIGANDS DIFFUSABLES D'AMYLOIDE-ß UTILISANT DES COMPOSÉS D'ACYLHYDRAZIDE
US8962677B2 (en) 2007-07-12 2015-02-24 Acumen Pharmaceuticals, Inc. Methods of restoring cognitive ability using non-peptidic compounds
GB0719559D0 (en) 2007-10-05 2007-11-14 Senexis Ltd Compounds
EP2650308A3 (fr) 2007-10-05 2014-11-12 Genentech, Inc. Utilisation d'anticorps anti-beta amyloide aux maladies oculaires
WO2009048539A2 (fr) 2007-10-05 2009-04-16 Genentech, Inc. Anticorps monoclonal
BRPI0818621A8 (pt) 2007-10-05 2018-01-30 Ac Immune Sa composição farmacêutica, e, métodos para reduzir a carga da placa e a quantidade de placas na camada de célula de gânglio retinal de um indivíduo, para prevenir, tratar e/ou aliviar os efeitos de uma doença ocular, para diagnosticar uma doença ocular e uma predisposição a uma doença ocular, para monitorar doença ocular, para predizer responsividade de um paciente, e para reter ou diminuir pressão ocular nos olhos de um indivíduo
CN101152576A (zh) 2007-10-15 2008-04-02 王延江 防治阿尔茨海默病的药物
WO2010011947A2 (fr) 2008-07-25 2010-01-28 Abbott Laboratories Analogues du peptide ss-amyloïde, oligomères de celui-ci, procédés de préparation et compositions comprenant lesdits analogues ou oligomères, et leurs utilisations
US20100173828A1 (en) 2008-07-25 2010-07-08 Abbott Gmbh & Co. Kg Aß(X - 38 .. 43) oligomers, and processes, compositions, and uses thereof
ES2665495T3 (es) 2009-02-25 2018-04-26 Academia Sinica Anticuerpos anti-CemX capaces de unirse a mIgE humana sobre linfocitos B
EP2558494B1 (fr) 2010-04-15 2018-05-23 AbbVie Inc. Protéines de liaison à la bêta amyloïde
US9062101B2 (en) 2010-08-14 2015-06-23 AbbVie Deutschland GmbH & Co. KG Amyloid-beta binding proteins

Patent Citations (50)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4399216A (en) 1980-02-25 1983-08-16 The Trustees Of Columbia University Processes for inserting DNA into eucaryotic cells and for producing proteinaceous materials
US4634665A (en) 1980-02-25 1987-01-06 The Trustees Of Columbia University In The City Of New York Processes for inserting DNA into eucaryotic cells and for producing proteinaceous materials
US5179017A (en) 1980-02-25 1993-01-12 The Trustees Of Columbia University In The City Of New York Processes for inserting DNA into eucaryotic cells and for producing proteinaceous materials
US4510245A (en) 1982-11-18 1985-04-09 Chiron Corporation Adenovirus promoter system
US4816397A (en) 1983-03-25 1989-03-28 Celltech, Limited Multichain polypeptides or proteins and processes for their production
US5168062A (en) 1985-01-30 1992-12-01 University Of Iowa Research Foundation Transfer vectors and microorganisms containing human cytomegalovirus immediate-early promoter-regulatory DNA sequence
US4968615A (en) 1985-12-18 1990-11-06 Ciba-Geigy Corporation Deoxyribonucleic acid segment from a virus
EP0436597A1 (fr) 1988-09-02 1991-07-17 Protein Eng Corp Production et selection de proteines de liaison diversifiees de recombinaison.
US5837500A (en) 1988-09-02 1998-11-17 Dyax, Corp. Directed evolution of novel binding proteins
US5571698A (en) 1988-09-02 1996-11-05 Protein Engineering Corporation Directed evolution of novel binding proteins
US5403484A (en) 1988-09-02 1995-04-04 Protein Engineering Corporation Viruses expressing chimeric binding proteins
US5223409A (en) 1988-09-02 1993-06-29 Protein Engineering Corp. Directed evolution of novel binding proteins
EP0368684A1 (fr) 1988-11-11 1990-05-16 Medical Research Council Clonage de séquences d'immunoglobulines de domaines variables.
US5939598A (en) 1990-01-12 1999-08-17 Abgenix, Inc. Method of making transgenic mice lacking endogenous heavy chains
US5580717A (en) 1990-05-01 1996-12-03 Affymax Technologies N.V. Recombinant library screening methods
US5427908A (en) 1990-05-01 1995-06-27 Affymax Technologies N.V. Recombinant library screening methods
WO1991017271A1 (fr) 1990-05-01 1991-11-14 Affymax Technologies N.V. Procedes de triage de banques d'adn recombine
EP0527839A1 (fr) 1990-05-01 1993-02-24 Affymax Technologies N.V. Procedes de triage de banques d'adn recombinant
EP0589877A1 (fr) 1990-07-10 1994-04-06 Cambridge Antibody Tech Procede de production de chainon de paires a liaison specifique.
WO1992020791A1 (fr) 1990-07-10 1992-11-26 Cambridge Antibody Technology Limited Methode de production de chainons de paires de liaison specifique
WO1992001047A1 (fr) 1990-07-10 1992-01-23 Cambridge Antibody Technology Limited Procede de production de chainon de paires a liaison specifique
US5969108A (en) 1990-07-10 1999-10-19 Medical Research Council Methods for producing members of specific binding pairs
WO1992002551A1 (fr) 1990-08-02 1992-02-20 B.R. Centre Limited Procedes de production de proteines presentant une fonction souhaitee
US5627052A (en) 1990-08-02 1997-05-06 B.R. Centre, Ltd. Methods for the production of proteins with a desired function
US5545806A (en) 1990-08-29 1996-08-13 Genpharm International, Inc. Ransgenic non-human animals for producing heterologous antibodies
US5625126A (en) 1990-08-29 1997-04-29 Genpharm International, Inc. Transgenic non-human animals for producing heterologous antibodies
US5569825A (en) 1990-08-29 1996-10-29 Genpharm International Transgenic non-human animals capable of producing heterologous antibodies of various isotypes
US5633425A (en) 1990-08-29 1997-05-27 Genpharm International, Inc. Transgenic non-human animals capable of producing heterologous antibodies
US5877397A (en) 1990-08-29 1999-03-02 Genpharm International Inc. Transgenic non-human animals capable of producing heterologous antibodies of various isotypes
US5661016A (en) 1990-08-29 1997-08-26 Genpharm International Inc. Transgenic non-human animals capable of producing heterologous antibodies of various isotypes
US5814318A (en) 1990-08-29 1998-09-29 Genpharm International Inc. Transgenic non-human animals for producing heterologous antibodies
US5770429A (en) 1990-08-29 1998-06-23 Genpharm International, Inc. Transgenic non-human animals capable of producing heterologous antibodies
WO1992009690A2 (fr) 1990-12-03 1992-06-11 Genentech, Inc. Methode d'enrichissement pour des variantes de l'hormone de croissance avec des proprietes de liaison modifiees
US5885793A (en) 1991-12-02 1999-03-23 Medical Research Council Production of anti-self antibodies from antibody segment repertoires and displayed on phage
WO1996033735A1 (fr) 1995-04-27 1996-10-31 Abgenix, Inc. Anticorps humains derives d'une xenosouris immunisee
WO1996034096A1 (fr) 1995-04-28 1996-10-31 Abgenix, Inc. Anticorps humains derives de xeno-souris immunisees
WO1997008320A1 (fr) 1995-08-18 1997-03-06 Morphosys Gesellschaft Für Proteinoptimierung Mbh Banques de proteines/(poly)peptides
WO1997029131A1 (fr) 1996-02-09 1997-08-14 Basf Aktiengesellschaft ANTICORPS HUMAINS SE FIXANT AU FACTEUR NECROSANT DES TUMEURS DE TYPE $g(a)
WO1998024893A2 (fr) 1996-12-03 1998-06-11 Abgenix, Inc. MAMMIFERES TRANSGENIQUES POSSEDANT DES LOCI DE GENES D'IMMUNOGLOBULINE D'ORIGINE HUMAINE, DOTES DE REGIONS VH ET Vλ, ET ANTICORPS PRODUITS A PARTIR DE TELS MAMMIFERES
WO1998031700A1 (fr) 1997-01-21 1998-07-23 The General Hospital Corporation Selection de proteines a l'aide de fusions arn-proteine
US6218506B1 (en) 1997-02-05 2001-04-17 Northwestern University Amyloid β protein (globular assembly and uses thereof)
WO1998047343A2 (fr) 1997-04-04 1998-10-29 Biosite Diagnostics, Inc. Bibliotheques polyvalentes et polyclonales
WO1998049286A2 (fr) 1997-05-01 1998-11-05 Board Of Regents, The University Of Texas System Evolution orientee d'enzymes et d'anticorps
WO1999036569A1 (fr) 1998-01-20 1999-07-22 The Board Of Trustees Of The University Of Illinois Proteines pour la presentation de la surface d'une cellule de levure et leurs utilisations
WO1999045962A1 (fr) 1998-03-13 1999-09-16 Genpharm International, Inc. Animaux transgeniques capables de fabriquer des anticorps heterologues
WO1999053049A1 (fr) 1998-04-15 1999-10-21 Abgenix, Inc. Production d'anticorps humains par des epitopes et formation de profils d'expression genique
WO2000056772A1 (fr) 1999-03-25 2000-09-28 Knoll Gmbh Anticorps humains se liant a l'interleukine-12 humaine et procedes de production de ces derniers
WO2001010900A2 (fr) 1999-08-04 2001-02-15 University Of Southern California PROTEINE D'AMYLOIDE β (ENSEMBLE GLOBULAIRE ET SES UTILISATIONS)
WO2003016467A2 (fr) 2001-08-17 2003-02-27 Eli Lilly And Company Utilisation d'anticorps ayant une forte affinite pour le peptide a$g(b) dans le traitement de pathologies et de maladies liees a a$g(b)
WO2003016466A2 (fr) 2001-08-17 2003-02-27 Eli Lilly And Company Anticorps anti-$g(a)$g(b)

Non-Patent Citations (99)

* Cited by examiner, † Cited by third party
Title
ALBERT, S.E. ET AL., J. IMMUNOL., vol. 159, 1997, pages 1393 - 1403
ARAI, K. ET AL., J. IMMUNOL. METHODS, vol. 217, 1998, pages 79 - 85
ARISPE ET AL., PNAS, vol. 90, 1993, pages 567
AUSUBEL, F.M. ET AL.: "Current Protocols in Molecular Biology", 1989, GREENE PUBLISHING ASSOCIATES
BABCOCK, J.S. ET AL., PROC. NATL. ACAD. SCI. USA, vol. 93, 1996, pages 7843 - 7848
BARBAS ET AL., PNAS, vol. 88, 1991, pages 7978 - 7982
BIRD ET AL., SCIENCE, vol. 242, 1988, pages 423 - 426
BOCHER, W.O. ET AL., IMMUNOLOGY, vol. 96, 1999, pages 634 - 641
BOMBIL, F. ET AL., IMMUNOBIOL., vol. 195, 1996, pages 360 - 375
BOSS, M.A.; WOOD, C. R., IMMUNOLOGY TODAY, vol. 6, 1985, pages 12 - 13
BROWN ET AL., J BIOL CHEM, vol. 255, 1980, pages 4980 - 83
BROWN ET AL., J. LMMUNOL, vol. 127, 1981, pages 539 - 46
C. MASTERS ET AL., PNAS, vol. 82, 1985, pages 4245 - 4249
C. RUSSO ET AL., NATURE, vol. 405, 2000, pages 531 - 532
C.A. MCLEAN ET AL., ANN. NEUROL., vol. 46, 1999, pages 860 - 866
C.L. MASTERS ET AL., PNAS, vol. 82, 1985, pages 4245 - 4249
CHAMAT, S. ET AL., J. INFECT. DISEASES, vol. 180, 1999, pages 268 - 277
CHOI ET AL., J. NEUROSCI., vol. 7, 1987, pages 357 - 368
CLARKSON ET AL., NATURE, vol. 352, 1991, pages 624 - 628
D.J. SELKOE, NEURON, vol. 32, 2001, pages 177 - 180
D.'SCHENK., NAT. REV. NEUROSCI., vol. 3, 2002, pages 824 - 828
D.W. DICKSON ET AL., NEUROBIOL. AGING, vol. 16, 1995, pages 285 - 298
E. A. LERNER, YALE J. BIOL. MED., vol. 54, 1981, pages 387 - 402
E.B. LEE ET AL., JBS, vol. 278, 2003, pages 4458 - 4466
EREN, R. ET AL., IMMUNOLOGY, vol. 93, 1998, pages 154 - 161
FISHWILD, D. M. ET AL., NATURE BIOTECHNOLOGY, vol. 14, 1996, pages 845 - 851
FUCHS ET AL., BIOLTECHNOLOGY, vol. 9, 1991, pages 1370 - 1372
G. GALFRE ET AL., NATURE, vol. 266, 1977, pages 550 - 52
GALLO, M.L. ET AL., EUR. J. IMMUNOL., vol. 30, 2000, pages 534 - 540
GARRAD ET AL., BIO/TECHNOLOGY, vol. 9, 1991, pages 1373 - 1377
GEFTER ET AL., SOMATIC CELL GENET.
GOEDDEL: "Gene Expression Technology: Methods in Enzymology", 1990, ACADEMIC PRESS, pages: 185
GRAM ET AL., PNAS, vol. 89, 1992, pages 3576 - 3580
GREEN, L.L., J. IMMUNOL. METHODS, vol. 231, 1999, pages 11 - 23
GREEN, L.L.; JAKOBOVITS, A., J. EXP. MED., vol. 188, 1998, pages 483 - 495
GRIFFITHS ET AL., EMBO J, vol. 12, 1993, pages 725 - 734
HARDING, F.A.; LONBERG, N., ANN. N.Y. ACAD. SCI., vol. 764, 1995, pages 536 - 546
HARLOW, E., AND LANE, D.,: "Antibodies, A Laboratory Manual", 1988, COLD SPRING HARBOR LABORATORY, article "Antikorpern als Hilfsmittel in Labor und Klinik"
HAWKINS ET AL., J MOL BIOL, vol. 226, 1992, pages 889 - 896
HAY ET AL., HUM ANTIBOD HYBRIDOMAS, vol. 3, 1992, pages 81 - 85
HEARD, C. ET AL., MOLEC. MED., vol. 5, 1999, pages 35 - 45
HERZ, U. ET AL., INT. ARCH. ALLERGY IMMUNOL., vol. 113, 1997, pages 150 - 152
HOLLIGER, P. ET AL., PROC. NATL. ACAD. SCI. USA, vol. 90, 1993, pages 6444 - 6448
HOOGENBOOM ET AL., NUC ACID RES, vol. 19, 1991, pages 4133 - 4137
HUSE ET AL., SCIENCE, vol. 246, 1989, pages 1275 - 1281
HUSTON ET AL., PROC. NATI. ACAD. SCI. USA, vol. 85, 1988, pages 5879 - 5883
HUSTON ET AL., PROC. NATL. ACAD. SCI. USA, vol. 85, 1988, pages 5879 - 5883
HUTCHINS, W.A. ET AL., HYBRIDOMA, vol. 18, 1999, pages 121 - 129
J. NÄSLUND ET AL., PNAS, vol. 91, 1994, pages 8378 - 8382
J.R. ROBINSON,: "Sustained und Controlled Release Drug Delivery Systems", 1978, MARCEL DEKKER, INC.
JOHNNSON, B. ET AL., ANAL. BIOCHEM., vol. 198, 1991, pages 268 - 277
JOHNSSON, B. ET AL., J. MOL. RECOGNIT., vol. 8, 1995, pages 125 - 131
JÖNSSON, U. ET AL., ANN. BIOL. CLIN., vol. 51, 1993, pages 19 - 26
JÖNSSON, U. ET AL., BIOTECHNIQUES, vol. 11, 1991, pages 620 - 627
KABAT ET AL.: "Sequences of Proteins of lmmunological Interest, Fifth Edition,", 1991, NIH PUBLICATION NR. 91-3242
KABAT, E.A. ET AL.: "Sequences of Proteins of Immunologicallnterest, Fifth Edition,", 1991, NIH PUBLICATION NR. 91-3242
KABAT, E.A. ET AL.: "Sequences of Proteins of Immunologieallnterest, Fifth Edition,", 1991, NIH PUBLICATION NR: 91-3242
KABAT, E.A. ET AL.: "Sequences of Proteins of lmmunological Interest, Fifth Edition,", 1991, NIH PUBLICATION NR. 91-3242
KIPRIYANOV, S.M. ET AL., HUMAN ANTIBODIES UND HYBRIDOMAS, vol. 6, 1995, pages 93 - 101
KIPRIYANOV, S.M. ET AL., MOL. IMMUNOL., vol. 31, 1994, pages 1047 - 1058
KNAPPIK ET AL., J. MOL. BIOL., vol. 296, 2000, pages 57 - 86
KOHLER; MILSTEIN, NATURE, vol. 256, 1975, pages 495 - 497
L.F. LUE ET AL., AM. J. PATHOL., vol. 155, 1999, pages 853 - 862
LÄMMLI UK, NATURE, vol. 227, 1970, pages 680 - 685
LASHUEL ET AL., NATURE, vol. 418, 2002, pages 291
LEADER, K.A. ET AL., IMMUNOLOGY, vol. 76, 1992, pages 229 - 234
LERNER, YALE J. BIOL. MED.
LLAN, E. ET AL., HEPATOLOGY, vol. 29, 1999, pages 553 - 562
LONBERG, N. ET AL., NATURE, vol. 368, 1994, pages 856 - 859
LONBERG, N.; HUSZAR, D., INT. REV. IMMUNOL., vol. 13, 1995, pages 65 - 93
LUNN, M.P. ET AL., J. NEUROCHEM., vol. 75, 2000, pages 404 - 412
M. L. GEFTER ET AL., SOMATIC CELL GENET., vol. 3, 1977, pages 231 - 36
M.P. LAMBERT ET AL., J. NEUROCHEM., vol. 79, 2001, pages 595 - 605
M.P. LAMBERT ET AL., PNAS, vol. 95, 1998, pages 6448 - 6453
MACQUITTY, J.J.; KAY, R.M., SCIENCE, vol. 257, 1992, pages 1188
MCCAFFERTY ET AL., NATURE, vol. 348, 1990, pages 552 - 554
MENDEZ, M. J. ET AL., NATURE GENETICS, vol. 15, 1997, pages 146 - 156
MURPHY, W.J. ET AL., CLIN. IMMUNOL., vol. 90, 1999, pages 22 - 27
MURPHY, W.J. ET AL., SEMIN. IMMUNOL., vol. 8, 1996, pages 233 - 241
N. SERGEANT ET AL., J. OF NEUROCHEMISTRY, vol. 85, 2003, pages 1581 - 1591
NGUYEN, H. ET AL., MICROBIOL. IMMUNOL., vol. 41, 1997, pages 901 - 907
POLJAK, R.J. ET AL., STRUCTURE, vol. 2, 1994, pages 1121 - 1123
R. H. KENNETH: "Monoclonal Antibodies: A New Dimension In Biological Analyses", 1980, PLENUM PUBLISHING CORP.
R.D.TERRY ET AL., ANN.NEUROL. 30., 1991, pages 572 - 580
R.J. KAUFMAN; P.A. SHARP, MOL. BIOL., vol. 159, 1982, pages 601 - 621
REISNER, Y; DAGAN, S., TRENDS BIOTECHNOL., vol. 16, 1998, pages 242 - 246
ROBERTS, R.W.; SZOSTAK, J.W., PROC. NATL. ACAD. SCI. USA, vol. 94, 1997, pages 12297 - 12302
ROES, J. ET AL., J. IMMUNOL. METHOD, vol. 183, 1995, pages 231 - 237
SAMBROOK, FRITSCH UND MANIATIS: "Molecular Cloning; A Laboratory Manual, Second Edition,", 1989, COLD SPRING HARBOR
SMITHSON, S.L. ET AL., MOL. IMMUNOL., vol. 36, 1999, pages 113 - 124
T.C. SAIDO ET AL., NEURON, vol. 14, 1995, pages 457 - 466
TAYLOR, L.D. ET AL., NUCL. ACIDS RES., vol. 20, 1992, pages 6287 - 6295
TAYLOR, L.D. ET AL., NUCLEIC ACIDS RES., vol. 20, 1992, pages 6287 - 6295
URLAUB; CHASIN, PROC. NATL. ACAD. SCI. USA, vol. 77, 1980, pages 4216 - 4220
WARD ET AL., NATURE, vol. 341, 1989, pages 544 - 546
YANG, X.D. ET AL., J. LEUKOC. BIOL., vol. 66, 1999, pages 401 - 410
YEH ET AL., INT. J. CANCER, vol. 29, 1982, pages 269 - 75
YEH ET AL., PNAS, vol. 76, 1976, pages 2927 - 31
YOSHINARI, K.; ARAI, K., HYBRIDOMA, vol. 17, 1998, pages 41 - 45

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JP2012250981A (ja) 2012-12-20
CA2514582C (fr) 2018-04-10
ES2567437T3 (es) 2016-04-22
JP2007524574A (ja) 2007-08-30
EP1594891B1 (fr) 2016-01-13
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CN1768076A (zh) 2006-05-03
CA3000519A1 (fr) 2004-08-12
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